Formulations of 4-Methyl-5-(Pyrazin-2-yl)-3H-1,2-Dithiole-3-Thione, and Methods of Making and Using Same

ABSTRACT

This disclosure provides, among other things, compositions comprising quantities of oltipraz crystals, as well as method of making such compositions, and method of treating patients using such compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to Indian Application No. 201611031045,filed Sep. 12, 2016, and U.S. Provisional Application No. 62/412,681,filed Oct. 25, 2016. The entire contents of each application, includingtheir specifications, claims and drawings, are expressly incorporatedherein by reference.

FIELD

The disclosure herein relates to new pharmaceutical compositionscomprising the compound4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione (depicted in FormulaI below), as well as methods of making and using such formulations. Thecompound, which is also known as oltipraz, has known uses in the medicalfield.

BACKGROUND

Mucositis is the painful inflammation and ulceration of mucous membranesoften caused by chemo-/radio-therapy for cancer. Mucositis typicallyoccurs in the gastrointestinal (GI) tract, e.g. in the oral (e.g.buccal) cavity. Oral and gastrointestinal (GI) mucositis is a common,painful side-effect of patients undergoing treatments such as high-dosechemotherapy, hematopoietic stem cell transplantation and the like.

Lesions of mucositis are characterized by mucosal breakdown resulting inextensive, deep ulcerations. Among granulocytopenic cancer patients, theloss in mucosal integrity created by ulceration results in thegeneration of a portal of entry for indigenous oral bacteria that oftenleads to sepsis or bacteremia. Mucositis occurs to some degree in morethan one third of patients receiving anti-neoplastic drug therapy. Thefrequency and severity are significantly greater among patients who aretreated with induction therapy for leukemia or with many of theconditioning regimens for hematopoietic stem cell marrow transplant.Moderate to severe mucositis occurs in virtually all patients whoreceive radiation therapy for tumors of the head and neck and typicallybegins with cumulative exposures of 20 Gy and then worsens as totaldoses of 60 Gy or more are reached.

Clinically mucositis progresses through three stages:

1. Early, painful mucosal erythema, which can be palliated with localanesthetics or non-narcotic analgesics.

2. Painful ulceration with pseudomembrane formation. Pain is often ofsuch intensity as to require parenteral narcotic analgesia.

3. Spontaneous healing, occurring about 2-4 weeks after cessation ofanti-neoplastic therapy.

To date, therapy for mucositis is predominantly palliative and focusedon pain control and maintenance of nutrition. For example, oralmucositis is in practice often addressed only by palliative measuressuch as improvements in oral hygiene, alone or in combination withanalgesic therapy such as administration of lidocaine. Such approacheshave typically low efficacy and are insufficient for addressing severecases of mucositis. Even opioids are often insufficient to controlmucositis pain. Various pharmaceutical therapies for mucositis have beenproposed however to date there remains a clear need for improvedtreatments for mucositis. In this context, oltipraz(4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione) has been suggestedas a potential candidate. See, e.g., Fahl et al. PCT/US2001/014464(published as WO2001085142) and Prendergast PCT/EP2008/052969 (publishedas WO 2008/110585).

The properties of known forms of oltipraz render its use impractical asa treatment, however. Oltipraz is known to exist in crystalline form. Todate, however, known crystalline oltipraz formulations, which areprepared by recrystallizing oltipraz (see, e.g., WO2016207914), comprisea mixture of oltipraz crystals of varying sizes up to millimeters inlength along the longest axis, which crystals are highly insoluble inwater and have poor bioavailability when administered topically ororally. Accordingly, there is a need for new formulations of oltiprazthat have improved properties for treating conditions such as mucositis.There is also a need for new pharmaceutical compositions and dosageforms of oltipraz.

SUMMARY

The inventors have surprisingly found that the properties of crystallineoltipraz can be improved by formulating compositions in which crystalparameters including particle size are controlled. By controlling thecrystal particle size and formulation, crystals of oltipraz are providedthat have prolonged size-stability in aqueous suspension and improvedaqueous solubility as compared to previously known forms of oltiprazsuch as recrystallized oltipraz prepared according to the processdisclosed in WO2016207914. For example, the inventors have found thatformulations comprising crystals of oltipraz that are of a controlled,much smaller size have beneficial properties such as excellent stabilityin the form of a dry composition and/or the ability to be readilyre-suspended in aqueous compositions to form substantially homogeneousdispersions of oltipraz crystals that typically exhibit substantiallyimproved solubility, size-stability and/or efficacy compared to otherforms of oltipraz known in the art. Further, unlike recrystallizedoltipraz, the formulations disclosed herein can increase the geneexpression of glutathione peroxidase 4 (GPX4) and/or myeloperoxidase(MPO) in a human or non-human animal patient, as well as decrease thegene expression of Peroxiredoxin 2 (PRDX2) in a human or non-humananimal patient. The new forms and compositions of oltipraz crystals havetherapeutic uses for example in the treatment of mucositis, and in thisregard, the new forms and compositions of oltipraz crystals exhibitimproved beneficial properties compared to such recrystallized oltipraz.

This disclosure therefore provides crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione having a MHD of from30 to 2000 nm. As described in more detail below, the term ‘MHD’ is ameasure of particle size and refers to the intensity averaged, meanhydrodynamic diameter (Z-average) as determined by the cumulants fittingof dynamic light scattering. The crystals have improved solubility inaqueous solution compared to previous crystal forms of oltipraz and whencomprised in pharmaceutical compositions provide for increasedtherapeutic efficacy.

The disclosure also provides compositions comprising quantities ofcrystals of 4-methyl-5-(pyrazin-2-yl)-3H-1, 2-dithiole-3-thione. Incertain embodiments the crystals have an intensity averaged, meanhydrodynamic diameter (Z-average) as determined by dynamic lightscattering (DLS) in a range of from 30 to 2000 nm. (For convenience, inthis disclosure the dimension of “intensity averaged, mean hydrodynamicdiameter (Z-average) as determined by the cumulants fitting of dynamiclight scattering” data is abbreviated as “MHD” and the precise method bywhich DLS measurements can be made to determine the MHD are providedbelow.) Usually, the crystals have a MHD of from 30 to 1200 nm; moreoften from 100 to 700 nm and still more typically from 150 to 450 nm orfrom 400 nm to 700 nm or from 400 nm to 600 nm. In certain embodiments,the crystals have a MHD within a target range of from 30 to 100, 100 to1200 nm, 150 to 600 nm, 150 to 450 nm, 400 nm to 700 nm, 400 nm to 600nm or 450 to 550 nm.

The compositions typically comprise at least one stabilizing agent thatstabilizes the crystals such that they retain a MHD within a targetrange of from 100 to 2000 nm if left in water at 25° C. for a period offrom 1 to 24 hours, such as a period of 1 hour, 6 hours, or 24 hours.Usually, the stabilized crystals retain a MHD in a target range of 30 to100, 100 to 1200 nm, 150 to 600 nm, 150 to 450 nm, 400 to 700 nm, 400 to600 nm or 450 to 550 nm if left in water at 25° C. for a period of fromabout 1 to about 24 hours, such as about 6 hours. Usually, thestabilized crystals will retain a MHD in a target range of 30 to 100,100 to 1200 nm, 150 to 600 nm, 150 to 450 nm, 400 to 700 nm, 400 to 600nm, or 450 to 550 nm if left in water at 25° C. for a period of 1 hour,6 hours, or 24 hours. Typically, the stabilizing agent is one or more ofa polymer, a surfactant and/or a bulking agent. In certain embodiments,the crystals are stabilized by a combination of stabilizing agents suchas a polymer and surfactant, which together act to stabilize thecrystals.

This disclosure provides dry and liquid compositions comprising crystalsas defined herein. The dry compositions can be mixed with water and/oranother liquid to provide a liquid composition of such crystals. Thisdisclosure also provides methods of making such dry and liquidsuspensions. This disclosure also provides dry compositions, including,e.g., spray-dried or lyophilized compositions, prepared from aqueouscompositions comprising the crystals and a bulking agent. Thisdisclosure also provides pharmaceutical compositions comprising suchcrystals. This disclosure further provides pharmaceutical containers forpreparing and administering a dose of a liquid pharmaceuticalcomposition comprising crystals as described herein. This disclosurealso provides methods of treating human and non-human animal patientswith pharmaceutical compositions disclosed herein. Further provided arecrystals as described herein and compositions comprising such crystalsfor use in the treatment of a patient such as a human or non-humananimal. This disclosure also provides crystals as described herein andcompositions comprising such crystals for use in the manufacture of amedicament for the treatment of a patient in need thereof, such as ahuman or non-human animal.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1 and 2 are respectively a correlogram and an intensity sizedistribution for a DLS analysis of a sample of suspended crystals. Therelaxation time is 1180 microseconds, Z-ave is 403 nm, and the PdI is0.364.

FIG. 3a is a scanning electron microscopy (SEM) image at 5000Xmagnification of a composition comprising oltipraz described in Example2 prior to stability testing.

FIG. 3b is a SEM image at 5000× magnification of the dry compositiondescribed in Example 2 after stability testing for three months at 40°C. and 75% RH.

FIG. 3c is a SEM image at 1500× magnification of the dry compositiondescribed in Example 2 after stability testing for three months at 40°C. and 75% RH.

FIG. 4A is a graph of the mean percentage of weight change in the oralmucositis assessment described in Example 3. FIG. 4B is a graph of themean daily mucositis scores in the oral mucositis assessment describedin Example 3.

FIG. 5 is a graph of the chi-square analysis of the percent of animaldays with a mucositis score≥3 in the oral mucositis assessment describedin Example 3.

FIG. 6 is an illustration of the five aqueous suspensions described inExample 4 comprising formulated oltipraz compositions. FIG. 6illustrates the effect of different bulking agents on the stability ofthe oltipraz crystals in an aqueous suspension.

FIG. 7 is a graph showing the effect of hydrogen peroxide (H2O2) on theviability of primary human gingival epithelial cells (HGEPp).

FIG. 8 is a graph showing the effect of recrystallized oltipraz,formulated oltipraz composition as described herein, and a controlpowder on H2O2-induced oxidative stress in HGEPp cells.

FIG. 9 is a graph showing the effect of recrystallized oltipraz andformulated oltipraz composition as described herein on the production ofreactive oxygen species (ROS) in HGEPp cells.

DETAILED DESCRIPTION A. Overview of the Compositions Comprising Crystalsof 4-METHYL-5-(PYRAZIN-2-YL)-3H-1,2-DITHIOLE-3-THIONE

The disclosure provides crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione (“oltipraz”) having aMHD of from 30 to 2000 nm. The disclosure also provides compositionscomprising such crystals (i.e. compositions comprising a quantity ofsuch crystals), and methods for the production of such crystals andcompositions comprising them.

As noted above, the compositions and methods of this disclosure relateto crystals of 4-methyl-5-(pyrazin-2-yl)-3H-1, 2-dithiole-3-thionehaving an MHD in the range of from 30 to 2000 nm, such as from 30 to1200 nm, e.g. 100 to 600 nm, 400 to 700 nm, 400 to 600 nm, preferably150 to 450 nm, 400 to 700 nm, 400 to 600 nm or 450 to 550 nm.

Certain embodiments of the compositions and methods described hereincomprise a quantity of crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione having an MHD in therange of from 30 to 100, 100 to 200 nm, with embodiments having MHD' swithin target ranges of from 30 to 100, 100 to 1200 nm, 150 to 600 nm,150 to 450 nm, 400 to 700 nm, 400 to 600 nm or 450 to 550 nm. The MHD ofthe crystals may be measured in any number of ways known to skilledartisans, including dynamic light scattering as described herein. Asmentioned above, the compound4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione, also known asoltipraz, can be prepared in crystalline form. Embodiments of thecrystal compositions provided herein, however, have been found toprovide dry compositions of oltipraz crystals that are stable forextended periods, and which are able to be readily re-suspended inaqueous compositions to form substantially homogeneous dispersions ofoltipraz crystals that exhibit substantially improved properties ascompared to the previously available crystalline form.

The oltipraz crystals in the compositions described herein typicallyalso exhibit substantially increased rate of dissolution and solubilityin water, e.g., at 20° C., as compared to oltipraz crystals preparedfrom standard methods (e.g., ranging from 20 μm to 200 μm or greater).For example, the oltipraz crystals in the compositions of thisdisclosure typically have a solubility in water at 20° C. between 100and about 250% that of crystals of oltipraz, prepared fromrecrystallization and having diameters of 20 to 200 μm. More typically,oltipraz crystals in the compositions of this disclosure have asolubility of from about 130 to about 220%, such as from about 160% toabout 200% e.g. from about 170 to about 190% that of oltipraz crystalsof 20 to 200 μm in diameter.

As discussed in Example 5 below, the solubility of oltipraz in water at20° C. in certain embodiments of compositions disclosed herein is almostdouble that of the larger oltipraz crystals (e.g., a >80% increase).Solubility values of >3.5 μg/ml, >4.0 μg/ml, >4.5 μg/ml, >5.0 μg/mland >5.5 μg/ml are all possible, including, e.g., about 5.1 μg/ml, about5.2 μg/ml, about 5.3 μg/ml, about 5.4 μg/ml, about 5.5 μg/ml, about 5.6μg/ml, and about 5.7 μg/ml. Hence, solubility values in water at 20° C.in the following exemplary ranges are possible: 3.5 μg/ml to 8.0 μg/ml,3.5 μg/ml to 7.0 μg/ml, 3.5 μg/ml to 6.0 μg/ml, 3.5 μg/ml to 5.7 μg/ml,4.0 μg/ml to 8.0 μg/ml, 4.0 μg/ml to 7.0 μg/ml, 4.0 μg/ml to 6.0 μg/ml,4.0 μg/ml to 5.7 μg/ml, 4.5 μg/ml to 8.0 μg/ml, 4.5 μg/ml to 7.0 μg/ml,4.5 μg/ml to 6.0 μg/ml, 4.5 μg/ml to 5.7 μg/ml, 5.0 μg/ml to 8.0 μg/ml,5.0 μg/ml to 7.0 μg/ml, 5.0 μg/ml to 6.0 μg/ml, 5.0 μg/ml to 5.7 μg/ml,5.5 μg/ml to 8.0 μg/ml, 5.5 μg/ml to 7.0 μg/ml, 5.5 μg/ml to 6.0 μg/ml,5.5 μg/ml to 5.7 μg/ml, 6.0 μg/ml to 6.5 μg/ml, 6.0 μg/ml to 7.0 μg/ml,6.0 μg/ml to 8.0 μg/ml, 6.5 μg/ml to 7.0 μg/ml, 6.5 μg/ml to 8.0 μg/ml,7.0 μg/ml to 8.0 μg/ml, and greater than 8.0 μg/ml.

Typically, therefore, the oltipraz crystals in the compositions of thisdisclosure have a solubility in water at 20° C. of from about 3.5 toabout 8 μg/ml, more typically from about 4 to about 7.5 μg/ml, such asfrom about 4.5 to about 7 μg/ml e.g. from about 5 to about 6.5 μg/mlsuch as from about 5.5 to about 6 μg/ml, e.g. about 5.7 μg/ml.

The crystals of this disclosure can be prepared by processing oltiprazinto crystals having the desired size range using processes as describedbelow. In some circumstances, once the desired size is attained,however, the crystals in aqueous or other liquid solution will tend togrow larger over time, e.g., by agglomerating and/or recrystallizing toform larger crystals. Hence, in instances where it is desired to preventthe crystals from growing larger for a period of time, at least onestabilizing agent may be added to the composition in order to helpmaintain the crystals in the desired size range in the liquid solution.

Typically, the stabilizing agent is a polymer, which may be used aloneor in combination with one or more other stabilizing agents such assurfactants, to stabilize the individual crystals by inhibiting and/orpreventing, for at least a period of time, the formation of largercrystals, e.g., through agglomeration, ripening (e.g. Ostwald ripening),and/or recrystallization. In certain embodiments, the polymer can be apolymer that comprises charged moieties. In other embodiments, thepolymer may be neutral. Sometimes, one or more surfactants may beemployed as stabilizing agents, either alone or together with a polymer.Various polymers and/or surface active molecules can have an affinityfor the oltipraz crystal surface, e.g., such that they can coat, adsorb,adhere or otherwise associate with all or a portion of the crystals andthereby interfere with the crystals agglomerating, ripening, and/orrecrystallizing to form larger crystals.

As noted above, the quantity of crystals in the liquid suspension thenmay be further treated to produce a dry composition, e.g., by mixing abulking agent with a liquid composition of crystals and then removingthe liquid from the composition to form a dry composition, e.g., byspray-drying or lyophilizing an aqueous composition. The bulking agentcan also serve as a stabilizing agent, either alone or in combinationwith other stabilizing agents. When a bulking agent is used, the drycomposition thus will comprise both the crystalline drug and the bulkingagent, as well as any other stabilizing agents or other ingredients thatare present in the liquid composition prior to the removal of the waterand/or other liquid solvent. When the dry composition is then mixed withliquid (e.g., water), the drug crystals and other ingredients present inthe dry composition will then be released into the liquid.

The term “dry composition” as used herein refers to a composition thatsubstantially excludes water or other solvent. As used in thisdisclosure, the term “substantially” is intended to encompass both“wholly” and “largely but not wholly.” Thus, a dry composition thatsubstantially excludes water is a composition that wholly excludes water(and/or other solvent) or largely excludes water (and/or other solvent).That is, the dry composition either has no water or solvent, or at mostonly a small or residual amount of water or solvent such that thecomposition is not moist or wet.

B. Liquid Compositions Comprising Crystals in Suspension

Any suitable method can be used to produce the oltipraz crystals of thisdisclosure. For example, oltipraz crystals can be wet milled in thepresence of at least one stabilizing agent that can help to stabilizethe drug crystals to reduce or prevent the growth of crystals byagglomeration, ripening and/or recrystallization. The wet milling ofoltipraz crystals in the presence of the stabilizing agent thus createsa liquid (e.g., aqueous) composition comprising the oltipraz crystals insuspension in the composition. Combinations of stabilizing agents may beadded to the wet milling composition to facilitate stabilization of thecrystals.

Alternatively, the oltipraz crystals may be made by other methods ofproducing nanocrystals, e.g., by antisolvent precipitation,supercritical fluid precipitation, printing techniques adapted from thesemiconductor industry, or three dimensional printing or other knownmeans of producing nanoparticles.

For example, a liquid composition comprising at least a portion of thecrystals of this disclosure and optionally other additives, e.g., from awet milling or antisolvent process, can be admixed with a bulking agentto form a liquid composition comprising the bulking agent and crystalsin suspension. In certain embodiments, a liquid composition comprisingat least a portion of the crystals and other additives, e.g., from a wetmilling or antisolvent process, is then admixed with a bulking agent toform a liquid composition comprising the bulking agent and crystals insuspension. That liquid composition then may be processed to remove theliquid, e.g., by spray-drying or lyophilization in the case of aqueoussolutions, and additional drying if necessary, to form a dry compositionthat substantially excludes water. Other processes known to personsskilled in the art also may be used to prepare dry compositionscomprising the crystals. For example, the liquid composition can besprayed onto sugar spheres or beads for drying. When dry, the sugarspheres or beads become a dissolvable carrier for the drug and otheradditives, e.g., the stabilizing agent(s) and/or bulking agent(s). Thedry composition thus comprises the oltipraz crystals and any ingredientsother than the liquid solvent (e.g., water) that were present in theliquid composition. The dry composition can be then later admixed with aliquid comprising water, at which time the bulking agent can facilitaterelease of the crystals to again form an aqueous composition comprisingsuch crystals in suspension. Any additional nonvolatile ingredientspresent in the liquid composition prior to removal of water or othersolvent will be carried along in the dry composition and also releasedinto the re-suspended aqueous composition.

Depending on the amount of water and/or other liquid solvent used in themilling or other nanocrystal production process such as antisolventprecipitation, the oltipraz crystals can be present in an amount rangingfrom 2% or less to 40% or more by weight of the liquid composition priorto the addition of any bulking agent. Within that range are included thefollowing ranges in percent by weight of 1-20%, 2 to 5%, 5 to 10%, 10 to15%, 10 to 20%, 15 to 20%, 15 to 25%, 15 to 30%, 20 to 30%, 25 to 35%,30 to 40%, or more than 40%. In some embodiments, the crystals can bebetween 6 and 11% by weight of the liquid composition, e.g., between 7and 10%. In certain such embodiments, the concentration of the crystalsin the liquid is about 1% to about 30% by weight, about 4% to about 15%by weight, about 5% to about 10% by weight, about 6% to about 10% byweight, about 6% to about 12% by weight, about 7% to about 10% byweight, about 8% to about 10% by weight, or about 8.6% by weight of thesuspension. Accordingly, the liquid composition typically comprisesbetween about 1 to about 40 wt %, such as from about 2 to about 20 wt %,e.g. from about 4 to about 15 wt %, typically from about 6 to about 12wt % such as from about 7 to about 10 wt % e.g. about 8 to about 9 wt %such as about 8.6 wt % of oltipraz crystals, based on the weight of theliquid composition prior to the addition of any bulking agent.

Alternatively, the amount of crystals can be calculated as a percent ofthe components other than the water or other liquid solvent in thecomposition prior to addition of a bulking agent. As a percent of thenon-solvent components, the crystals can be present in an amount rangingless than 10% up to more than 60% by weight of the non-solventcomponents prior to the addition of any bulking agent. Within that rangeare included the following ranges in percent by weight of 1 to 5%, 5 to10%, 10 to 15%, 15 to 20%, 20 to 30%, 25 to 40%, 30 to 40%, 40 to 50%,50 to 60%, 60 to 70%, and over 70% . In certain embodiments, thecrystals comprise between 30 and 70%, e.g., between 50 and 65%, orbetween 55 and 60%, or about 57% by weight of the non-solvent componentsprior to addition of any bulking agent. Accordingly, the non-solventcomponents in the composition typically comprise from about 1 to about70 wt % oltipraz crystals based on the overall weight of the non-solventcomponents in the composition; more typically the non-solvent componentscomprise from about 30 to about 65 wt % such as from about 50 to about60 wt % e.g. from about 55 to about 58 wt % such as about 57 wt % of thecomposition based on the overall weight of the non-solvent components inthe composition.

Once a bulking agent is added, the percentage by weight of the oltiprazcrystals typically will decrease. Within the liquid composition beforeremoval of water or other liquid solvent but after addition of thebulking agent, the crystals may comprise from 1% up to 10% or more ofthe liquid composition. Within such ranges are, e.g., 1 to 2%, 1 to 3%,2 to 3%, 2 to 4%, 2 to 5%, 2 to 6%, 3 to 5%, 3 to 6%, 3 to 7%, 4 to 7%,4 to 8%, 5 to 9% and 6 to 10%. In some embodiments, the crystals cancomprise between 2 and 6% of the liquid suspension comprising thebulking agent, e.g., between 3 and 5%, or about 4%. In certain suchembodiments, the concentration of the crystals in the liquid is about0.1% to about 4% by weight, about 0.2% to about 3.5% by weight, about0.5% to about 3.5% by weight, about 1% to about 3.5% by weight, about1.5% to about 3% by weight, about 2% to about 3% by weight, or about2.5% by weight of the formulation. Accordingly, the concentration ofoltipraz crystals in the liquid is typically from about 0.1 to about 10wt % (based on the weight of the liquid composition before removal ofwater or other liquid solvent but after addition of a bulking agent ifpresent), more often from about 0.5 to about 8 wt % e.g. from about 1 toabout 6 wt % such as from about 2 wt % to about 5 wt % such as fromabout 2.5 wt % to about 4 wt %.

Alternatively, the amount of the crystals can be calculated as a percentof the non-solvent (e.g., non-water) components following addition of abulking agent. This percentage of oltipraz in the non-solvent componentsalso may be referred to as the “drug loading” percentage because itrepresents the amount of the oltipraz crystals in the dry composition.As a percent of the non-solvent components, i.e., the solids, theoltipraz crystals can be present in an amount ranging from less than 2%up to 25% or more. Within that range are included the following rangesin percent by weight of 0.5 to 1%, 1% to 2%, 2 to 4%, 3 to 5%, 4 to 7%,5 to 8%, 5 to 10%, 6 to 8%, 6 to 9%, 6 to 10%, 7 to 11%, 7 to 12%, 8 to12%, 8 to 13%, 9 to 13%, 9 to 14%, 10 to 15%, 11 to 16%, 12 to 17%, 13to 18%, 14 to 19%, 15 to 20% and 20 to 25%. Accordingly, the oltiprazcrystals are typically from about 0.5 to about 25 wt % (based on theweight of the non-solvent components after addition of a bulking agentif present), more often from about 1 to about 25 wt % such as from about5 to about 20 wt % e.g. from about 6 to about 19 wt %, such as fromabout 10 to about 18 wt % e.g. about 15 to about 17 wt % such as about16 wt % (e.g. about 16.7 wt %). The crystals can comprise between about5% and about 10% by weight of the non-solvent components, e.g., betweenabout 6% and about 9%, such as about 7%. For example, in certainembodiments the crystals can comprise between 5 and 10% by weight of thenon-solvent components, e.g., between 6 and 9%, or about 7%. In otherembodiments the crystals comprise between 10 and 20% by weight of thepowder, e.g., between 13 and 17%, e.g., about 15% by weight of thenon-solvent components.

In some embodiments, a dry composition comprising a drug loading ofabout 15% will provide good results when reconstituted with water, i.e.,the dry composition quickly forms a dispersion (e.g., less than aminute) with moderate or gentle shaking, with the crystals substantiallyretaining their MHD from prior to drying. Typically, a dry compositioncomprising a drug loading of about 20% or higher provides less desirableresults when reconstituted with water, i.e., the dry composition slowlyforms a dispersion (e.g., several minutes) with moderate or vigorousshaking, and the dispersion may comprise larger particles, e.g., up to 2microns in size. In such cases, it is advantageous to reduce the drugloading to a lower level that provides the desired characteristics interms of rapidly forming a dispersion of crystals that retain theiroriginal MHD. Without being bound by any particular theory, it isbelieved that as the concentration of oltipraz crystals within the drycomposition approaches 20%, there is less of the other ingredients inthe composition (e.g., stabilizing agents and/or bulking agents) toseparate the individual crystals, which in turn leads to moreinteractions between the crystals, resulting in slower formation of adispersion in an aqueous or other solvent environment and also theformation of larger particles, e.g., by agglomeration. Hence,compositions comprising drug loadings of 12 to 20% a contemplated,including loadings of 12 to 13%, 12 to 14%, 12 to 15%, 13 to 14%, 13 to15%, 13 to 16%, 14 to 15%, 14 to 16%, 14 to 17% 15 to 16%, 15 to 17%, 15to 18%, 16 to 17%, 16 to 18%, 16 to 19%, 17 to 18%, 17 to 19%, 17 to20%, 18 to 19%, 18 to 20%, including drug loadings of about 12%, about13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%and about 20% are all contemplated. Accordingly, the dry compositiontypically has a drug loading of about 12 to about 20 wt % such as fromabout 14 to about 18 wt % e.g. from about 15 to about 17 wt % such asabout 16 or about 16.7 wt %.

Stabilizing Agents

As mentioned above, liquid compositions comprising the oltipraz crystalsof this disclosure typically also comprise one or more stabilizingagents to stabilize the crystals. In some circumstances, in the absenceof at least one stabilizing agent (or a combination of agents thattogether act to stabilize), over time oltipraz crystals in liquidsuspension can agglomerate, ripen, and/or recrystallize to form largercrystals. It is typically desirable to maintain the crystals in the sizerange that results from the wet milling, antisolvent precipitation orother crystal-production processes for a period of time, e.g., to permitstorage of the materials prior to the next step in processing, or toallow testing or validation of crystal size or some other feature of abatch of oltipraz crystals. In such instances, at least one stabilizingagent may be provided to the liquid composition of crystals, e.g.,during and/or after milling, or during and/or after antisolventprecipitation, in order to stabilize the crystals to thereby preventand/or inhibit the milled crystals from agglomerating, recrystallizingand/or ripening to form larger crystals. Thus, any agent that eitheralone or in combination with another agent serves to stabilize thecrystals to thereby prevent and/or inhibit the milled crystals fromagglomerating, recrystallizing and/or ripening to form larger crystals,is deemed a stabilizing agent. If a combination of two or more agents isused to stabilize crystals, then each of the two or more co-stabilizersis deemed to be a stabilizing agent even though an individual agentwithin the combination may be unable to stabilize the crystals byitself, or unable to stabilize the crystals by itself for the desiredlength of time.

Alternatively, if the oltipraz crystals are to be quickly converted to adry form, e.g., by mixing with a bulking agent and being spray-dried orlyophilized, a stabilizing agent may be unnecessary. This may be anacceptable alternative if the intended method of administration does notrequire the oltipraz crystals to later have stability upon resuspensionin water, e.g., if the resuspension will occur immediately beforeadministration of the dry composition, e.g., in pill or tablet form.Alternatively, a single agent such as povidone or PVP-VA64(polyvinylpyrrolidone vinyl acetate, a copolymer of1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6:4 by mass,commercially available e.g. from BASF as Product No. 95405-2-43), may beable to serve both as a stabilizing agent and as bulking agent, therebyrendering additional stabilizing agents unnecessary and providing acomposition that will exhibit stability upon resuspension in waterand/or other liquid.

Generally speaking, stabilizing agents are surface active agents thataffect the surface of the crystals in some way. While not wishing to bebound to a particular theory by which a stabilizing agent can operate tostabilize the crystals, it is believed that the stabilization typicallycan take one of two forms. Steric stabilization can be accomplished bymixing the crystals with either an amphiphilic or water-soluble materialthat interacts with the crystal surface, which keeps crystal faces frominteracting by providing a barrier between crystals. This is typicallyaccomplished by addition of polymer, surfactant, or both. Alternatively,electrostatic stabilization can be accomplished by modifying the crystalsurface with a charge through addition of a charged compound (polymer,surfactant, or other interacting charged molecule or ion). Because allor at least many of the crystals then carry the same charge, in theorythey repel each other, thereby increasing the energy barrier requiredfor two crystal faces to get close enough to fuse together.

Typically, the stabilizing agent maintains the size of the crystals inthe liquid composition within a specified size range for a period oftime following wet milling. Such a period can be on the order of hours,e.g., at least 1 hour, at least 6 hours, at least 12 hours, at least 24hours, at least two days, at least three days, at least a week, at leasttwo weeks, at least a month, at least two months, and at least sixmonths, or longer.

Typically, the stabilizing agent comprises a polymer that is eitherneutral or capable of associating charged moieties with the individualmilled oltipraz crystals, e.g., by coating the crystals, or adsorbing orotherwise associating with them. Such polymers thus may be neutral ormay include moieties that provide either a positive or negative chargeto the polymer, and in that way the charged moieties associated with thecrystals may be able to repel other crystals having like charges ontheir surfaces. Nonionic, cationic or anionic polymers may be used asstabilizing agents, including especially pharmaceutically acceptablenonionic, cationic and anionic polymers. Combinations of such polymersalso may be employed. Sometimes, the stabilizing agent may comprise acarbohydrate and/or protein, e.g., albumin.

The polymer may be an acrylate polymer comprised of a plurality ofrepeat units derived from identical or different monomers. Acrylatepolymers comprising different types of repeat units are referred toherein as “copolymers”. Exemplary repeat units of acrylate polymersinclude repeat units derived from methacrylate, alkyl acrylate (such asmethyl acrylate or ethyl acrylate), hydroxyethyl methacrylate,ethylacrylate, butyl methacrylate, acrylonitrile, or alkylcyanoacrylates. Typically, when the carboxylic acid functionality ofacrylate is not protected as an ester, the acid can exist as aprotonated carboxylic acid (—COOH) or as an anionic salt (e.g., —COONa).

The polymer also may be an acrylate- and alkenyl ether-based co-polymer(e.g., Carbopol® type polymers such as Carbopol 974P NF),polyvinylpyrrolidine (e.g., PVP K15 or K30), a cellulosic polymer suchas a cationic hydroxyethyl cellulose (e.g., in the Polymer JR family),hydroxypropylcellulose (HPC e.g. HPC EF typically having a molecularweight of about 80 kDa), or hydroxypropyl methylcellulose (HPMC e.g.HMPC E3 typically having viscosity of about 3 cP at 2% in water), orhydroxypropyl methylcellulose acetate succinate, HPMCAS. The polymeralso may be a copovidone (e.g., PVP-VA64), poly(ethylene oxide), or apoloxamer (e.g., a poly(propylene oxide) and poly(ethylene oxide)copolymer). The polymer also may be an acrylamide polymer. For example,the polymer may be comprised of repeat units derived from acrylamide.

The repeat units can be functionalized by adding groups that can changethe permeability, hydrophobicity, or other properties of theformulation. For example, certain repeat units can be functionalized bytertiary amines or by quaternary amines, such as quaternarytrialkylammonium substituents.

An acrylate polymer may be comprised of repeat units derived from amethacrylate monomer. In certain embodiments, the acrylate polymercomprises repeat units derived from an acrylate monomer and repeat unitsderived from a methacrylate monomer. Typically, the acrylate polymercomprises repeat units derived from ethyl acrylate and repeat unitsderived from methyl methacrylate. Typically, some of the ethyl acrylatemonomeric units are functionalized on the ethyl group by atrimethylammonium chloride group. The acrylate polymer of the crystalmay be poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2.Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethylmethacrylate chloride) 1:2:0.2 may be sold as EUDRAGIT® RL Otherpolymethacrylate-based copolymers in the Eudragit family may be used,e.g., Eudragit S, L, E or RS.

Typically, the polymer is one or more of an acrylate- and alkenylether-based co-polymer, polyvinylpyrrolidone, hydroxypropylcellulose,hydroxypropyl methylcellulose, a copovidone such as PVP-VA64, and apolymethacrylate-based copolymer such as EUDRAGIT® RL. More often, thepolymer is one or more of a copovidone such as PVP-VA 64 and apolymethacrylate-based copolymer such as EUDRAGIT® RL.

Alternatively, or in addition to the above polymers, other surfaceactive ingredients may be added to the liquid compositions that comprisethe crystals for the purpose of helping to stabilize the crystals insuspension. In addition to helping stabilize the crystals suchsurfactants also may aid in the dispersion of crystals and/or otheringredients in a particular liquid composition. Indeed, such surfactantsmay be added solely for the purpose of aiding in the dispersion ofcrystals and/or other ingredients in the liquid compositions describedherein that are prepared from the dry compositions described herein.

Surfactants suitable for use in the compositions described herein may beionic or non-ionic. These include, but are not limited to: sodiumisostearate, cetyl alcohol, polysorbates (Polysorbate 20, Polysorbate40, Polysorbate 60, Polysorbate 80), steareth-10 (Brij 76), sodiumdodecyl sulfate (sodium lauryl sulfate), lauryl dimethyl amine oxide,cetyltrimethylammonium bromide (CTAB), polyethoxylated alcohols,polyoxyethylene sorbitan, octoxynol, N,N-dimethyldodecylamine-N-oxide,hexadecyltrimethylammonium bromide (HTAB), polyoxyl 10 lauryl ether,bile salts (such as sodium deoxycholate or sodium cholate), polyoxylcastor oil, nonylphenol ethoxylate, cyclodextrins, lecithin, dimethiconecopolyol, lauramide DEA, cocamide DEA, cocamide MEA, oleyl betaine,cocamidopropyl betaine, cocamidopropyl phosphatidyl PG-dimoniumchloride, dicetyl phosphate (dihexadecyl phosphate), ceteareth-10phosphate, methylbenzethonium chloride, dicetyl phosphate, ceteth-10phosphate (ceteth-10 is the polyethylene glycol ether of cetyl alcoholwhere n has an average value of 10; ceteth-10 phosphate is a mixture ofphosphoric acid esters of ceteth-10), ceteth-20, Brij S10 (polyethyleneglycol octadecyl ether, average M_(n)˜711), PEG-20 phytosterol, andPoloxamers (including, but not limited to, Poloxamer 188(HO(C₂H₄O)_(a)(CH(CH₃)CH₂O)_(b)(C₂H₄O)_(a)H, average molecular weight8400) and Poloxamer 407 (HO(C₂H₄O)_(a)(CH(CH₃)CH₂O)_(b)(C₂H₄O)_(a)H,wherein a is about 101 and b is about 56)). Poloxamers are nonionictriblock copolymers composed of a central hydrophobic chain ofpolyoxypropylene (poly(propylene oxide)) flanked by two hydrophilicchains of polyoxyethylene (poly(ethylene oxide)). Poloxamer surfactants,also sold under the trade name of Pluronic surfactants, thus may beemployed, e.g., Pluronic F-68, which also is known as Poloxamer 188. Thesurfactants that may be used in the formulation may be non-ionicsurfactants such as polyoxyethylene glycol alkyl ethers (e.g.,octaethylene glycol monododecyl ether, pentaethylene glycol monododecylether, and polyethylene glycol alkyl ethers such as Brij® Detergents),polyoxypropylene glycol alkyl ethers, glucoside alkyl ethers (e.g.,decyl glucoside, lauryl glucoside, or octyl glucoside), polyoxyethyleneglycol alkylphenol ethers (e.g. Triton X-100, Nonoxyol-9), glycerolalkyl esters, polyoxyethylene glycol sorbitan alkyl esters (e.g.,polysorbates), sorbitan alkyl esters, cocamides, and Poloxamers(mentioned above). In certain embodiments, the non-ionic surfactant maybe polyoxyethylene (20) sorbitan monooleate (polysorbate 80).Polysorbate 80 is available under the tradename Tween 80.

Typically, the surfactant is one or more of poloxamers such as PluronicF-68 (i.e., Poloxamer 188), polysorbates such as polysorbate 80 (Tween80), povidone based polymers, lecithin, PEG-castor oil derivatives,TPGS, bile acids, tyloxapol, acacia, and sodium lauryl sulfate. Moretypically, the surfactant is polysorbate 80 (Tween 80).

As described in more detail below, appropriate combinations or mixturesof surfactants such as those above may also be used, either with orwithout out other stabilizing agents such as the polymers describedabove. For example, in certain embodiments the stabilizing agents cancomprise a combination of a neutral polymer and a neutral surfactant, acationic polymer and a neutral surfactant, or a neutral polymer and ananionic surfactant. As noted above, however, such stabilizing agents maybe unnecessary when the bulking agent also acts as a stabilizing agentor when no stabilizing agent is desired.

When such stabilizing agents are employed, then depending on the amountof water and/or other solvent used in the milling process, thestabilizing agent(s) can be present in an amount ranging from less than1 percent to 25% or more by weight of the liquid composition prior tothe addition of any bulking agent. Within that range are included thefollowing ranges in percent by weight of 0.1 to 1%, 1 to 3%, 3 to 7%, 5to 10%, 5 to 15%, 5 to 20%, 10 to 15%, 10 to 20%, 10 to 25%, 15 to 20%,15 to 25%, 7.5 to 25%, or more than 25%. In some embodiments, thestabilizing agent(s) can comprise between 2 and 10%, e.g., between 4 and8% or about 6.4%. Accordingly, the amount of stabilizing agent(s) in theliquid composition prior to addition of any bulking agent is typicallyfrom about 0.1 to about 25 wt % such as from about 1 to about 20 wt %such as from about 2 to about 10 wt % e.g. from about 4 to about 8 wt %such as from about 5 to about 7 wt % e.g. about 6 wt % such as about 6.4wt %.

Alternatively, the amount of stabilizing agent can be calculated as apercent of the non-solvent components prior to addition of a bulkingagent. As a percent of the non-solvent components, the stabilizing agentcan be present in an amount ranging from 10 percent or less to 75% ormore by weight of the non-liquid components prior to the addition of anybulking agent. Within that range are included the following ranges inpercent by weight of 0.1 to 10%, 10 to 20%, 20 to 30%, 30 to 40%, 40 to50%, 50 to 60%, 60 to 75% or more. In some embodiments, the stabilizingagent can be between 30 and 55% by weight of the non-solvent components,e.g., between 35 and 50%, or between 40 and 45%, or about 42.7%.Accordingly, the amount of stabilizing agent(s) in the composition priorto addition of any bulking agent is typically from about 1 to about 75wt %, such as from about 10 to about 60 wt % such as from about 20 toabout 55 wt % e.g. from about 30 to about 50 wt % such as from about 40to about 45 wt % e.g. about 42 wt % such as about 42.7 wt %, based onthe weight of non-solvent components.

Once a bulking agent is added, the percentage by weight of thestabilizing agent(s) typically will decrease. Within the liquidcomposition before removal of water and/or other liquid solvent,following addition of a bulking agent the stabilizing agent(s) maycomprise from less than 1% up to 30% or more of the liquid composition,again depending on the amount of water or other solvent in thecomposition prior to a water removal step. Within such ranges are, e.g.,0.5 to 1%, 1 to 2%, 1 to 3%, 2 to 3%, 2 to 4%, 2 to 5%, 3 to 6%, 3 to7%, 4 to 7%, 4 to 8%, 5 to 9% and 6 to 10%, 10 to 15%, 15 to 20%, 20 to25%, 25 to 30% and more than 30%. In some embodiments, the stabilizingagent(s) can comprise between 1 and 5% by weight of the liquidsuspension comprising the bulking agent, e.g., about 2 to 4%, or about3.1%. Accordingly, the amount of stabilizing agent(s) in the liquidcomposition (based on the weight of the liquid composition beforeremoval of water or other liquid solvent but after addition of a bulkingagent if present), is typically from about 0.1 to about 30 wt %, such asfrom about 1 to about 10 wt % such as from about 2 to about 5 wt % e.g.from about 3 to about 4 wt % such as about 3.1 wt %.

Alternatively, the amount of stabilizing agent(s) can be calculated as apercent of the non-solvent components following addition of a bulkingagent. As a percent of the non-liquid components, the stabilizingagent(s) can be present in an amount ranging from less than 2% up to 20%or more. Within that range are included the following ranges in percentby weight of 2 to 4%, 3 to 5%, 4 to 7%, 5 to 8%, 5 to 10%, 6 to 8%, 6 to9%, 6 to 10%, 7 to 11%, 7 to 12%, 8 to 12%, 8 to 13%, 9 to 13%, 9 to14%, 10 to 15%, 11 to 16%, 12 to 17%, 13 to 18%, 14 to 19% and 15 to20%, and more than 20%. For example, in certain embodiments thestabilizing agent can comprise between 5 and 15% by weight of thenon-solvent components, e.g., between 9 and 13%, or about 11.2%. Suchamounts will also correspond to the amounts of the stabilizing agent inthe dry composition. Accordingly, the amount of stabilizing agent(s) inthe composition (based on the weight of non-solvent components afteraddition of a bulking agent if present), is typically from about 2 toabout 20 wt %, such as from about 4 to about 17 wt % such as from about8 to about 15 wt % e.g. from about 10 to about 12 wt % such as about 11wt % e.g. about 11.2 wt %.

Combinations of Stabilizing Agents

As noted above, combinations of stabilizing agents may be employed toassist in stabilizing the crystals in a liquid composition and/or assistin dispersing the crystals from a dry composition. For example, as notedabove, in certain embodiments, nonionic surfactants may be combined witha cationic polymer or an anionic polymer. In other embodiments, an ionicsurfactant (anionic or cationic) is combined with a neutral polymer.Other embodiments can combine a neutral polymer and nonionic surfactant.

Some exemplary combinations include, with or without an anti-foamingagent such as simethicone, (i) Eudragit RL in combination with Tween 80,Pluronic F-68 and/or sodium lauryl sulfate, (ii) Carbopol 974P NF RL incombination with Tween 80, Pluronic F-68 and/or sodium lauryl sulfate,(iii) PVP (K15 or K30) RL in combination with Tween 80, Pluronic F-68and/or sodium lauryl sulfate, (iv) HPC EF RL in combination with Tween80, Pluronic F-68 and/or sodium lauryl sulfate, and (v) HPMC E3 RL incombination with Tween 80, Pluronic F-68 and/or sodium lauryl sulfate.Some examples of such combinations are illustrated in Table 1 below.

TABLE 1 Components Formulation Composition (mg/mL) Function Name 1 2 3 45 6 API Oltipraz 50 50   50 50 50 50 Stabilizing Eudragit RL 25 AgentCarbopol 974P  5* (Polymer) NF PVP (K15 or 25 K-30) HPC EF 25 25 HPMC E325 Stabilizing Tween 80 12.5 12.5 Agent Pluronic F68 12.5 12.5 12.5(Surfactant) SLS 12.5 Anti-foam Simethicone 0.5  0.5 0.5 0.5 0.5 0.5*Added after milling

Among the various combinations, Eudragit RL in combination with Tween 80or HPC EF in combination with Tween 80 have been found by the Inventorsto provide acceptable results and typically to be particularlybeneficial in terms of forming and keeping small crystals stable for aperiod of time. As discussed below, other combinations of the foregoingpolymers and surfactants may be suitable depending on the particularcomposition and method of administration. The amounts of the individualcomponents in such combinations are as set forth above for theindividual components.

Other Surface Active Agents

As noted above, surface active agents, including those listed above, maybe added to the liquid compositions described herein for purposes otherthan stabilizing oltipraz crystals, e.g., to aid in the dispersion ofcrystals upon resuspension with water and/or other liquid, or to serveother purposes beyond stabilizing the crystals, e.g., emulsifiers andanti-foam agents. For example, such ingredients can be added for thepurpose of improving processes and/or compositions such as the processesfor making the crystals or the properties of the composition comprisingcrystals.

In certain embodiments, e.g., an emulsifier may be added. Suitableemulsifiers include, but are not limited to, glycine soja protein,sodium lauroyl lactylate, polyglyceryl-4diisostearate-polyhydroxystearate-sebacate, behentrimoniummethosulfate-cetearyl alcohol, non-ionic emulsifiers like emulsifyingwax, polyoxyethylene oleyl ether, PEG-40 stearate, carbomer, cetostearylalcohol (cetearyl alcohol), ceteareth-12, ceteareth-20, ceteareth-25,ceteareth-30, ceteareth alcohol, Ceteth-20 (Ceteth-20 is thepolyethylene glycol ether of cetyl alcohol where n has an average valueof 20), oleic acid, oleyl alcohol, glyceryl stearate, PEG-75 stearate,PEG-100 stearate, and PEG-100 stearate, ceramide 2, ceramide 3, stearicacid, cholesterol, laureth-12, steareth-2, and steareth-20, orcombinations/mixtures thereof, as well as cationic emulsifiers likestearamidopropyl dimethylamine and behentrimonium methosulfate, orcombinations/mixtures thereof.

In certain embodiments, an anti-foam agent may be added. Anti-foamagents may be used to reduce the formation of foam, e.g., in the processof making the crystals. Anti-foam agents that may be used include, butare not limited to, oil-based anti-foam agents [e.g., a hydrophobicsilica or a wax (e.g., paraffin, ester waxes, fatty alcohol waxes,ethylene bis(stearamide)) in mineral or vegetable oil], powderdefoamers, water-based defoamers (e.g., long chain fatty alcohols, fattyacid soaps, or esters in a white oil or vegetable oil), silicone-baseddefoamers [hydrophobic silica in silicone oil], polyethylene glycol- orpolypropylene glycol-based defoamers, or alkyl polyacrylates. In certainpreferred embodiments, the anti-foam agent is a silicone-based anti-foamagent. In certain embodiments, the anti-foam agent ispoly(dimethylsiloxane), or silicon dioxide (simethicone).

Depending on the amount of water and/or other liquid used in the millingprocess, prior to the addition of a bulking agent, such additionalsurface active ingredient(s) can be present in cumulative amountsranging from less than 1 to more than 10% by weight of the liquidsuspension. Within that range are included the following ranges inpercent by weight, 0.1 to 1%, 1 to 3%, 1 to 4%, 1 to 5%, 2 to 5%, 2 to6%, 3 to 6%, 3 to 7%, 4 to 7%, 4 to 8%, 5 to 8%, 5 to 9%, and 6 to 10%,and greater than 10%. For example, an anti-foam agent can be in anamount from about 0.01% to about 2% by weight of the liquid compositioncomprising the crystals, e.g. from about 0.01% to about 2%, from about0.05% to about 1.5%, from about 0.1% to about 1%, from about 0.3% toabout 0.9%, or from about 0.4% to about 0.8% by weight of the crystal.Typically, an anti-foam agent can be present in an amount from about0.01% to about 2% by weight of the solid components (excluding bulkingagents if present) in the liquid composition comprising the crystals,e.g. from about 0.01% to about 2%, such as from about 0.05% to about1.5%, e.g. from about 0.1% to about 1%, such as from about 0.3% to about0.9%, e.g. from about 0.4% to about 0.8% by weight of the crystal.

For example, a composition comprising oltipraz crystals of thisdisclosure may typically comprise a combination of solubilizing agentsselected from (i) one or more of acrylate- and alkenyl ether-basedco-polymers, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, a copovidone such as PVP-VA64, and apolymethacrylate-based copolymer such as EUDRAGIT® RL; and (ii) one ormore of sodium lauryl sulfate, a poloxamer such as Pluronic F-68 andpolysorbate 80. Another surface active ingredient may also be presentsuch as an emulsifiers and/or an anti-foam agent. More typically thecomposition may comprise (i) one or more of a polymethacrylate-basedcopolymer such as Eudragit RL, an acrylate- and alkenyl ether-basedco-polymer such as Carbopol 974P NF; a polyvinylpyrrolidone such as PVP(K15 or K-30); a hydroxypropylcellulose such as HPC EF and ahydroxypropyl methylcellulose such as HPMC E3; (ii) one or more ofsodium lauryl sulfate, a poloxamer such as Pluronic F-68 and polysorbate80; and optionally (iii) an antifoam agent such aspoly(dimethylsiloxane) or silicon dioxide (simethicone). Still moretypically the composition may comprise (i) one or more of a copovidonesuch as PVP-VA64 and a polymethacrylate-based copolymer such asEUDRAGIT® RL; (ii) polysorbate 80 (Tween 80); and optionally (iii)simethicone. In such compositions, the amount of component (i) istypically from about 5 to about 40 wt %, preferably from about 20 toabout 35 wt % such as from about 25 to about 30 wt % based on the weightof solid components (excluding bulking agents) in the composition. Theamount of component (ii) is typically from about 10 to about 20 wt %,preferably from about 12 to about 18 wt % such as from about 14 to about15 wt % based on the weight of solid components (excluding bulkingagents) in the composition. If present, the amount of component (iii) istypically from about 0.1 to about 1 wt %, preferably from about 0.3 toabout 0.8 wt % such as from about 0.5 to about 0.7 wt % based on theweight of solid components (excluding bulking agents) in thecomposition.

Other Components

The liquid compositions described herein also can comprise liquids inaddition to water. For example, the liquid may be an aqueous buffersolution. Pharmaceutically acceptable buffers include acetate (e.g.,sodium acetate), sodium carbonate, citrate (e.g., sodium citrate),tartrate, glycylglycine, histidine, glycine, lysine, arginine, sodiumdihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, andtris(hydroxymethyl)-aminomethane or mixtures thereof. Alternatively, thecompositions described herein as aqueous compositions may be insteadprepared in a liquid solvent other than one that contains water, e.g., apolar organic solvent, such as methanol and/or ethanol. If liquids otherthan water are used, then advantageously, the liquid is one in whicholtipraz is not more than minimally soluble, e.g., not more than 0.35%,0.1%, 0.05%, 0.01%, 0.005%, 0.001%, or 0.0008% by weight solvatedoltipraz in solvent. Typically, therefore, if liquids other than waterare used, then advantageously, the liquid is one in which oltipraz isnot more than minimally soluble, e.g., the liquid does not support morethan 0.35%, e.g. not more than 0.1%, such as not more than 0.05%, e.g.not more than 0.01%, such as not more than 0.005%, e.g. not more than0.001% or 0.0008% by weight solvated oltipraz in solvent. Combinationsof liquids also may be used, including combinations of water and otherliquids such as one or more polar organic solvents. Hence, although itis contemplated that aqueous compositions can be used throughout thisdisclosure, it is also contemplated that the water component in any ofthe aqueous compositions described herein could be replaced in whole orin part by a liquid other than water. Where a solvent other than or inaddition to water is used, the percentages given above for thestabilizing agents and other ingredients typically remain the same orsubstantially the same.

Liquid compositions described herein, e.g., aqueous or otherwise, may beuseful for milling. Other liquid compositions described herein may beuseful for spray-drying or lyophilization-based methods of generatingthe crystals in a dry composition. The total concentration ofingredients in such liquid formulations may be represented by thepercentage by weight of combined solids in the formulation, wherein thecombined solids are the non-solvent components, e.g., the crystals andany additives such as a stabilizing agent, surfactant, and/or a bulkingagent that remain once the solvent is removed. The appropriate level ofsolids in a liquid composition as described herein can vary depending onthe use of the composition. For example, the total solids in acomposition that is undergoing wet milling may be higher or lower thanthe total solids in a composition that also comprises a bulking agentand is undergoing a process in which liquid is being removed, e.g.,spray-drying or lyophilization. In certain embodiments, for exampleincluding compositions for milling and/or spray-drying orlyophilization, the concentration of the solids in the liquid describedherein can be about 5% to about 35% or more by weight, including rangesof from 5 to 10%, 10 to 15%, 10% to 20%, 15 to 20%, 15 to 25%, 20 to25%, 20 to 30%, 25 to 30%, 25 to 35%, or more than 35%. In someembodiments, the total solids can be about 12% to about 18% by weight,about 13% to about 18% by weight, about 14% to about 17% by weight, orabout 16% by weight of the formulation. Typically, therefore, the totalsolids can be from about 12% to about 18% by weight, e.g. from about 13%to about 18% by weight, such as from about 14% to about 17% by weight,e.g. about 16% by weight of the formulation. Typically, in some liquidcompositions for milling, the total solids can be from about 20 to 30%by weight, e.g., from about 22 to about 27% by weight, such as about 25%by weight. In some embodiments, e.g., in some liquid compositions formilling, the total solids can be from about 20 to 30% by weight, e.g.,about 22 to 27% by weight, about 25% by weight. In some embodiments,e.g., spray-drying compositions, the total solids can be from about 25to 30% by weight, e.g., about 28% by weight. Using the guidance providedherein, one of ordinary skill will be able to determine an acceptablelevel of solids for compositions described herein.

Crystal Sizes and Distribution, such as Crystal Sizes and Distributionin Liquid Suspensions

Due to the inherent variability of the wet milling or othercrystal-forming process such as antisolvent precipitation, theindividual crystals of oltipraz formed from such processes willtypically vary in size, and thus a quantity of oltipraz crystalsproduced by such processes can typically be characterized by adistribution of crystals of varying sizes. When in an aqueoussuspension, the quantity of crystals described herein generally willhave a MHD of between 30 and 2000 nm. Generally speaking, largercrystals will tend to settle faster in aqueous compositions, and soquantities of smaller crystals, e.g., those having an MHD from 30 to 100nm, or 100 to 600 nm, including from 40 to 80 nm, 40 to 60 nm, or from150 to 450 nm, 400 to 700 nm, 400 to 600 nm, and 450 to 550 nm, oftenprovide an advantage in terms of better suspension characteristics overtime for an aqueous suspension of the crystals, e.g., the crystals willremain substantially completely suspended longer. Generally speaking,production of crystals by wet milling will have an MHD above 100 nm,although MHD values below 100 nm may be obtained with longer millingtimes and or different milling parameters. Methods such as antisolventprecipitation can produce crystal compositions having MHD values inranges below 100 nm, e.g., 30-100 nm, 40-80 nm and 40-60 nm. Within theMHD range of 30 to 2000 nm are MHD ranges of from 30 to 100 nm, 40 to 80nm, 40 to 60 nm, 100 to 250 nm, 100 to 1200 nm, 150 to 450 nm, 150 to600 nm, 200 to 500 nm, 200 to 520, 200 to 600 nm, 300 to 600 nm, 300 to700 nm, 300 to 800 nm, 400 to 600 nm, 400 to 700 nm, 800 nm, 500 to 750nm, 750 to 1000 nm, 1000 to 1500 nm, and from 1500 to 2000 nm.Accordingly, the oltipraz crystals of this disclosure typically have anintensity averaged (Z-average) MHD of from 30 to 1200 nm, such as from100 to 600 nm, e.g. from 150 to 450 nm, 400 to 700 nm, 400 to 600 nm or450 to 550 nm, e.g., from about 300 to 400 nm such as around 350 to 390nm or from 400 to 600 nm such as around 500 nm, as measured by DynamicLight Scattering.

It also is noted that the MHD measurements discussed herein also mayreflect the presence of any additional ingredients such as thestabilizing agent(s) to the extent that they are present in thecomposition with the crystals. As used herein, however, MHD measurementsobtained for complete aqueous dispersions comprising crystals and one ormore stabilizing agents, surfactants or other ingredients in the aqueousdispersion are deemed to be MHD measurements of the crystals themselves.

MHD can be determined by DLS using an appropriate instrument, e.g., aMalvern Zetasizer Nano-ZSP, using routine methods know to those skilledin the art. For example, the crystals can be put into an aqueoussuspension with deionized water to a concentration of 0.01 -0.1 mg(based on the weight of oltipraz) per mL prior to analysis. The resultwill be a transparent orange-red suspension. A backscatter)(173°detector can be used. The temperature should be set to 25° C. andsamples equilibrated for 90 seconds prior to analysis. The duration,number of runs, attenuator setting, and focal position can be setautomatically by the software. MHD values can be recorded withattenuator settings of 4-6 with mean count rates of 180-500 kcps.

All calculations of crystal size discussed herein can be performed inthe Malvern Zetasizer software. As noted above, average crystal sizesdiscussed herein are intensity-averaged mean hydrodynamic radius(Z-average). The size is calculated from the mean decay time of theautocorrelation function and the Stokes-Einstein equation. The viscosityof water at 25° C. (0.8872 cP) was used. In cases where a crystal sizedistribution is given, the Malvern General Purpose (normal resolution)method is used, which uses non-negative least squares (NNLS) fitting ofthe decay curves. The functioning of the Malvern Zetasizer can beperiodically checked using 100 nm polystyrene beads calibrationstandard. The relaxation time in the DLS experiment is between 600 and1500 microseconds with the preferred relaxation time between 500 and1300 microseconds.

The size calculation for the crystal sizes reported herein is based on acumulant method using the equation: Γq2=D=kBT/3πηd

where D is the diffusion coefficient calculated from the measured decayrate (Γ), kBT/3πηd is the Stokes-Einstein equation, d is the particlediameter, and q is the scattering wave vector which is dependent on thespecific instrument method parameters as listed above. The magnitude ofthe scattering wave vector is calculated according to the equation q=4Pi (refractive index of solvent) Sin(theta/2)/wavelength. The expecteddelay time will change if a different instrument uses a different valueof q. For calculations used herein, theta=173deg, a refractive index of1.333 for water is used, a laser wavelength of 633 nm yields a value forq=0.0264 nm{circumflex over ( )}(−1).

As discussed above, the inherent variability of the wet milling processmeans that the size of individual crystals in any given quantity ofcrystals will vary and thus a quantity of crystals prepared according tothis disclosure can be characterized by a distribution of crystals ofvarying sizes. One measure of the distribution of sizes is thepolydispersity index (PdI) of the crystals in the quantity. The formulafor determining PdI is:

PdI=(σ/d)²

where σ is the standard deviation and d is the mean hydrodynamicdiameter (Z-average)is less than 0.80, wherein PdI=(σ/d)², wherein σ isthe standard deviation and d is the mean hydrodynamic diameter(Z-average). Lower values of PdI indicate a more uniform distribution ofcrystals in a given quantity of crystals. Typically, oltipraz crystalsor quantities of such crystals in accordance with this disclosure have aPdI of less than 1, usually less than 0.8, often less than 0.6; forexample between 0.10 and 0.60, e.g. between 0.10 and 0.45, such asbetween 0.1 and 0.35 e.g. 0.1 and 0.25. Certain embodiments ofquantities of crystals in accordance with this disclosure can have a PdIof less than 1, less than 0.8, less than 0.6, e.g., between 0.10 and0.60, and between 0.10 and 0.45, 0.1 and 0.35 and 0.1 and 0.25.

Typically, therefore, this disclosure provides oltipraz crystals havingan intensity averaged (Z-average) MHD (as measured by Dynamic LightScattering) of from 30 to 1200 nm wherein the PdI of the crystals isfrom 0.1 to 0.6. More typically this disclosure provides oltiprazcrystals having an intensity averaged (Z-average) MHD of from about 100to about 600 nm wherein the PdI of the crystals is from 0.1 to 0.45.Still more typically this disclosure provides oltipraz crystals havingan intensity averaged (Z-average) MHD of from about 150 to about 450 nm,400 to 700 nm, 400 to 600 nm, or 450 to 550 nm, wherein the PdI of thecrystals is from 0.1 to 0.35.

FIGS. 1 and 2 illustrate a correlogram and intensity size distributionfor a DLS analysis of a sample of suspended crystals at 25° C. Therelaxation time is 1180 microseconds, MHD is 403 nm, and the PdI is0.364. It is noted that the x axis for both plots is logarithmic. TheMHD and PdI are both calculated by the instrument based on the dataobtained and are not determined visually from the figures.

C. Dry Compositions Comprising Crystals

As discussed above, the liquid compositions comprising crystals insuspension can be admixed with a bulking agent and then spray dried,lyophilized or otherwise processed to remove the water and/or otherliquid solvent to form a dry composition. The resulting dry compositioncan comprise particles that largely comprise the bulking agent and thuscan be much larger than the oltipraz crystals. For example, particles upto 200 microns (200,000 nm) or larger may be obtained. If desired, thesize of the particles obtained from processes such as spray drying maybe measured by scanning electron microscopy, laser diffraction or lightmicroscopy. Dry compositions prepared according to this disclosuregenerally will be in the form of an orange-red powder, and can beprepared with no discolorations or large particles or chinks visible.

Bulking Agents

The presence of a bulking agent reduces the likelihood ofcrystal-crystal surface contact in a dry composition such as aspray-dried or lyophilized powder, as direct contact can make thecrystals harder to re-suspend where the ultimate use of the compositionis resuspension in a liquid composition. Bulking agents that aregenerally very soluble in water may be able to release the crystals asindividual crystals upon resuspension. Accordingly, bulking agents thatare very soluble in water are typically used in compositions of thisdisclosure. Those skilled in the art are capable of choosing appropriatebulking agents based on the particular composition and intended route ofdelivery. Furthermore, because the bulking agent can be such a largefraction of the overall dry composition product, its properties mayaffect the rate of resuspension in water as well as potentiallyinfluence the taste of the composition if administered orally, possiblysignificantly.

One factor that can be evaluated to determine if a particular bulkingagent is appropriate for a particular embodiment includes whether thebulking agent does not alter the initial size of the crystals insuspension prior to removal of water, e.g., through spray dying orlyophilization. Where the intended use of the dry composition isresuspension with water or other liquid to make a liquid composition fororal or other form of administration, then advantageously, a bulkingagent is typically chosen that (i) does not yield large particles ofprecipitate upon resuspension with water, (ii) does not yield a drypowder that dissolves too slowly upon mixing with water, and (iii)yields a dry powder that is relatively stable to handling and storage,e.g., is not hygroscopic such that handling of the dry compositionbecomes difficult. Surface active agents may be added to theformulation, either in the liquid composition or to the dry compositionin order to enhance such properties in the dry composition. Suchproperties may be less important, however, if the dry composition is tobe formulated into a pill, tablet, capsule, gel capsule or the like fororal administration. Where the intended use of the dry composition isoral administration such as in a pill, tablet or capsule, then thebulking agent also should be evaluated on its ability to provide thedesired pharmacological profile following administration. If the smallercrystalline drug particles coated with a stabilizing agent are adsorbedonto the larger particles of the bulking agent during blending orgranulation, such as roller compaction, fluid bed, or high shear, then awater soluble bulking agent such as mannitol, or insoluble agent such asmicrocrystalline cellulose, may act as a carrier for those particles andaid the rate of dissolution from a capsule or a tablet.

As noted above, in principle, a bulking agent also can act as astabilizing agent. Examples of bulking agents include, but are by nomeans limited to, the group consisting of polyvinylpyrrolidones (e.g.,PVP K30 and PVP-VA64), cellulosic polymers such as HPC, HPMC, HPMC E3,Trehalose, and Dextrans such as Dextran 10 or Dextran 40. Examples ofbulking agents such as PVP-VA64 and HPC EF that provide acceptableresults for certain embodiments of this disclosure are provided herein.Most typically the bulking agent is PVP-VA64. Sometimes it is preferablethat the bulking agent is not Dextran 40. As noted above, appropriatebulking agents or combinations of bulking agents can be determined for aparticular composition and route of delivery. Factors such as theintended route of administration of the crystals (e.g., whether thecrystals are to be administered in a dry form such as a pill or capsuleor resuspended with a liquid such as water), all may be considered indetermining one or more acceptable bulking agents for a particularembodiment. Other factors such as the size and amounts of crystals, typeand quantity of stabilizing agent used (if any), the surfactants andamounts thereof (if any) that are employed, the amount of bulking agentto be used, the total solids in the liquid composition, the liquids inthe composition and any resuspension, and the process for removing water(and/or other liquid), also may be taken into account in determiningacceptable bulking agents or combinations of bulking agents.

In some circumstances use of Dextran 10 may provide a dry compositionthat provides particle sizes that are too large upon resuspension inwater. In other embodiments, HPMC may provide a composition thatdissolves more slowly than desired upon resuspension with water. In someembodiments, Trehalose can provide a composition that is morehygroscopic than desired for routine handling. Special packaging or theaddition of desiccant may be used to maintain the low water content ofsuch hygroscopic pharmaceutical compositions during stability on theshelf. Accordingly, it is sometimes preferable that the bulking agent isnot dextran 10 and/or is not HPMC and/or is not trehalose. In differentembodiments however, e.g., with different stabilizing agents,surfactants, or for a different intended route of administration, suchbulking agents can provide acceptable compositions.

Within the aqueous or liquid composition, depending on the amount ofliquid used, the bulking agent(s) can comprise from about 1 to 40% byweight or more of the composition. Within such ranges are, e.g., 1 to5%, 5 to 10%, 10 to 15%, 10 to 20%, 15 to 20%, 15 to 25%, 20 to 25%, 20to 30%, 25 to 30%, 25 to 35%, 30 to 35%, 30 to 40%. Depending on themethod chosen for removing water, the total solids in the compositionmay have to be maintained below a certain level to facilitate processingto a dry composition, e.g., in certain embodiments, below 30%, or about28%, and thus the amount of bulking agent(s) used may be limited by suchconsiderations. In certain embodiments, therefore, the bulking agent cancomprise between 15% and 25%, e.g., about 20 or 21%. Accordingly, thebulking agent(s) typically comprise from about 1 to about 40 wt % of theliquid composition, such as from about 10 to about 30 wt % e.g. fromabout 15 to about 25 wt % such as from about 20 to about 21 wt %.

Alternatively, as with the other ingredients, the amount of bulkingagent can be calculated as a percent of the solids, i.e., thenon-solvent components. As a percent of the solids, the bulking agent(s)can be present in amounts by weight ranging from less than 40% up to 98%or more, e.g., 40 to 50%, 50 to 60%, 55 to 65%, 60 to 70%, 60 to 75%, 60to 80%, 65 to 75%, 65 to 80%, 70 to 80%, 75 to 85%, 75 to 90%, 80 to90%, 80 to 95%, 85 to 95%, 90 to 98%, and greater than 98% by weight. Incertain embodiments, the bulking agent(s) can comprise between 65 and80% by weight of the total solids, e.g., between about 70 and 78%, e.g.,about 74% by weight of the total solids. Accordingly, the bulkingagent(s) typically comprise from about 40 to about 90 wt % of thenon-solvent (ie solid) composition, such as from about 65 to about 80 wt% e.g. from about 70 about 78 wt % such as from about 73 to about 75 wt%. Such amounts will also correspond to the amounts of the bulkingagent(s) in the dry composition.

The disclosure therefore provides crystals of oltipraz having a MHD offrom about 30 to about 2000 nm as measured by dynamic light scattering,wherein the crystals typically have a solubility in water at 20° C. offrom about 3.5 to about 8 μg/ml. More typically this disclosure providescrystals of oltipraz having a MHD of from about 100 to about 800 nm asmeasured by dynamic light scattering, wherein the crystals typicallyhave a solubility in water at 20° C. of from about 4.5 to about 7 μg/ml.Still more typically this disclosure provides crystals of oltiprazhaving a MHD of from 150 to about 450 nm, 400 to 700 nm, 400 to 600 nm,or 450 to 550 nm, as measured by dynamic light scattering, wherein thecrystals typically have a solubility in water at 20° C. of from about 5to about 6.5 μg/ml

The disclosure also provides a liquid composition comprising oltiprazcrystals according to this disclosure, wherein the composition does notcomprise a bulking agent, and wherein:

-   -   the composition comprises between about 1 to about 40 wt % of        oltipraz crystals, based on the weight of the liquid        composition;    -   the non-solvent components in the composition typically comprise        from about 1 to about 70 wt % oltipraz crystals; and    -   the composition comprises (i) from about 5 to about 40 wt %        (based on the weight of solid components in the composition) of        one or more of acrylate- and alkenyl ether-based co-polymers,        polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropyl        methylcellulose, a copovidone such as PVP-VA64, and a        polymethacrylate-based copolymer such as EUDRAGIT® RL;        and/or (ii) from about 10 to about 20 wt % % (based on the        weight of solid components in the composition) of one or more of        sodium lauryl sulfate, a poloxamer such as Pluronic F-68 and        polysorbate 80.

This disclosure also provides a liquid composition comprising oltiprazcrystals according to this disclosure, wherein the composition does notcomprise a bulking agent, and wherein

-   -   the composition comprises between about 4 to about 15 wt % of        oltipraz crystals, based on the weight of the liquid        composition;    -   the non-solvent components in the composition typically comprise        from about 50 to about 60 wt % oltipraz crystals;    -   the composition comprises (i) from about 20 to about 35 wt %        (based on the weight of solid components in the composition) of        one or more of a polymethacrylate-based copolymer such as        Eudragit RL, an acrylate- and alkenyl ether-based co-polymer        such as Carbopol 974P NF; a polyvinylpyrrolidone such as PVP        (K15 or K-30); a hydroxypropylcellulose such as HPC EF and a        hydroxypropyl methylcellulose such as HPMC E3; and/or (ii) from        about 12 to about 18 wt % % (based on the weight of solid        components in the composition) of one or more of sodium lauryl        sulfate, a poloxamer such as Pluronic F-68 and polysorbate 80;    -   the liquid solvent is water or an aqueous buffer solution; and    -   the composition optionally comprises from 0.1 to 1 wt % of        poly(dimethylsiloxane) or silicon dioxide (simethicone) based on        the non-solvent components in the composition.

This disclosure also provides a liquid composition comprising oltiprazcrystals according to this disclosure, wherein the composition does notcomprise a bulking agent, and wherein

-   -   the composition comprises between about 7 to about 10 wt % of        oltipraz crystals, based on the weight of the liquid        composition;    -   the non-solvent components in the composition typically comprise        from about 55 to about 58 wt % oltipraz crystals;    -   the composition comprises (i) from about 25 to about 30 wt %        (based on the weight of solid components in the composition) of        one or more of a copovidone such as PVP-VA64 and a        polymethacrylate-based copolymer such as EUDRAGIT® RL;        and/or (ii) from about 14 to about 15 wt % % (based on the        weight of solid components in the composition) of polysorbate 80        (Tween 80);    -   the liquid solvent is water; and    -   the composition optionally comprises 0.1 to 1 wt % simethicone        based on the non-solvent components in the composition.

The liquid composition comprising oltipraz crystals but not comprising abulking agent is typically suitable for milling.

The disclosure also provides a liquid composition comprising oltiprazcrystals according to this disclosure and a bulking agent, wherein

-   -   The concentration of oltipraz crystals in the liquid is from        about 0.1 to about 10 wt % based on the weight of the liquid        composition;    -   the non-solvent components in the composition typically comprise        from about 0.5 to about 25 wt % oltipraz crystals;    -   the composition comprises (i) from about 5 to about 40 wt %        (based on the weight of solid components excluding bulking        agents in the composition) of one or more of acrylate- and        alkenyl ether-based co-polymers, polyvinylpyrrolidone,        hydroxypropylcellulose, hydroxypropyl methylcellulose, a        copovidone such as PVP-VA64, and a polymethacrylate-based        copolymer such as EUDRAGIT® RL; and/or (ii) from about 10 to        about 20 wt % % (based on the weight of solid components        excluding bulking agents in the composition) of one or more of        sodium lauryl sulfate, a poloxamer such as Pluronic F-68 and        polysorbate 80; and    -   the composition comprises from about 1 to about 40 wt % (based        on the overall weight of the composition) of a bulking agent        selected from polyvinylpyrrolidones (e.g., PVP K30 and        PVP-VA64), cellulosic polymers such as HPC, HPMC, HPMC E3,        Trehalose, Dextrans (such as Dextran 10 or Dextran 40), PVP-VA64        and HPC EF.

This disclosure also provides a liquid composition comprising oltiprazcrystals according to this disclosure and a bulking agent, wherein

-   -   The concentration of oltipraz crystals in the liquid is from        about 1 to about 6 wt % based on the weight of the liquid        composition;    -   the non-solvent components in the composition typically comprise        from about 5 to about 20 wt % oltipraz crystals;    -   the composition comprises (i) from about 20 to about 35 wt %        (based on the weight of solid components excluding bulking        agents in the composition) of one or more of a        polymethacrylate-based copolymer such as Eudragit RL, an        acrylate- and alkenyl ether-based co-polymer such as Carbopol        974P NF; a polyvinylpyrrolidone such as PVP (K15 or K-30); a        hydroxypropylcellulose such as HPC EF and a hydroxypropyl        methylcellulose such as HPMC E3; and/or (ii) from about 12 to        about 18 wt % % (based on the weight of solid components        excluding bulking agents in the composition) of one or more of        sodium lauryl sulfate, a poloxamer such as Pluronic F-68 and        polysorbate 80;    -   the composition comprises from about 10 to about 30 wt % (based        on the overall weight of the composition) of a bulking agent        selected from PVP-VA64 and HPC EF;    -   the liquid solvent is water or an aqueous buffer solution; and    -   the composition optionally comprises from 0.1 to 1 wt % of        poly(dimethylsiloxane) or silicon dioxide (simethicone) based on        the non-solvent components (excluding the bulking agent) in the        composition.

This disclosure also provides a liquid composition comprising oltiprazcrystals according to this disclosure and a bulking agent, wherein

-   -   The concentration of oltipraz crystals in the liquid is from        about 2 to about 5 wt % based on the weight of the liquid        composition;    -   the non-solvent components in the composition typically comprise        from about 10 to about 18 wt % oltipraz crystals;    -   the composition comprises (i) from about 25 to about 30 wt %        (based on the weight of solid components excluding bulking        agents in the composition) of one or more of a copovidone such        as PVP-VA64 and a polymethacrylate-based copolymer such as        EUDRAGIT® RL; and/or (ii) from about 14 to about 15 wt % %        (based on the weight of solid components excluding bulking        agents in the composition) of polysorbate 80 (Tween 80); - the        composition comprises from about 15 to about 25 wt % (based on        the overall weight of the composition) of a bulking agent which        is PVP-VA64; - the liquid solvent is water; and - the        composition optionally comprises 0.1 to 1 wt % simethicone based        on the non-solvent components (excluding the bulking agent) in        the composition.

The liquid composition comprising oltipraz crystals according to thisdisclosure and a bulking agent is typically suitable for drying e.g.spray-drying.

The disclosure also provides a dry composition comprising oltiprazcrystals according to this disclosure and a bulking agent, wherein:

-   -   The percentage of oltipraz in the composition (i.e. the drug        loading) is from about 12 to about 20 wt %;    -   the composition comprises (i) from about 5 to about 40 wt %        (based on the weight of solid components excluding bulking        agents in the composition) of one or more of acrylate- and        alkenyl ether-based co-polymers, polyvinylpyrrolidone,        hydroxypropylcellulose, hydroxypropyl methylcellulose, a        copovidone such as PVP-VA 64, and a polymethacrylate-based        copolymer such as EUDRAGIT® RL; and/or (ii) from about 10 to        about 20 wt % % (based on the weight of solid components        excluding bulking agents in the composition) of one or more of        sodium lauryl sulfate, a poloxamer such as Pluronic F-68 and        polysorbate 80; and    -   the composition comprises from about 40 to about 90 wt % (based        on the overall weight of the composition) of a bulking agent        selected from polyvinylpyrrolidones (e.g., PVP K30 and        PVP-VA64), cellulosic polymers such as HPC, HPMC, HPMC E3,        Trehalose, Dextrans (such as Dextran 10 or Dextran 40), PVP-VA64        and HPC EF.

This disclosure also provides a dry composition comprising oltiprazcrystals according to this disclosure and a bulking agent, wherein:

-   -   The percentage of oltipraz in the composition (i.e. the drug        loading) is from about 14 to about 18 wt %;    -   the composition comprises (i) from about 20 to about 35 wt %        (based on the weight of solid components excluding bulking        agents in the composition) of one or more of a        polymethacrylate-based copolymer such as Eudragit RL, an        acrylate- and alkenyl ether-based co-polymer such as Carbopol        974P NF; a polyvinylpyrrolidone such as PVP (K15 or K-30); a        hydroxypropylcellulose such as HPC EF and a hydroxypropyl        methylcellulose such as HPMC E3; and/or (ii) from about 12 to        about 18 wt % % (based on the weight of solid components        excluding bulking agents in the composition) of one or more of        sodium lauryl sulfate, a poloxamer such as Pluronic F-68 and        polysorbate 80;    -   the composition comprises from about 65 to about 80 wt % (based        on the overall weight of the composition) of a bulking agent        selected from PVP-VA64 and HPC EF; and    -   the composition optionally comprises from 0.1 to 1 wt % of        poly(dimethylsiloxane) or silicon dioxide (simethicone) based on        the weight of solid components excluding bulking agents in the        composition

This disclosure provides a dry composition comprising oltipraz crystalsaccording to this disclosure and a bulking agent, wherein:

-   -   The percentage of oltipraz in the composition (i.e. the drug        loading) is from about 15 to about 17 wt %;    -   the composition comprises (i) from about 25 to about 30 wt %        (based on the weight of solid components excluding bulking        agents in the composition) of one or more of a copovidone such        as PVP-VA64 and a polymethacrylate-based copolymer such as        EUDRAGIT® RL; and/or (ii) from about 14 to about 15 wt % %        (based on the weight of solid components excluding bulking        agents in the composition) of polysorbate 80 (Tween 80); and    -   the composition comprises from about 70 to about 78 wt % (based        on the overall weight of the composition) of a bulking agent        which is PVP-VA64; and the composition optionally comprises 0.1        to 1 wt % simethicone based on the weight of solid components        excluding bulking agents in the composition.

The dry composition described above can be suspended in liquid to form aliquid suspension; typically the weight ratio of the solid:liquid isfrom about 1:10 to 1:200 such as from about 1:20 to 1:150 e.g. 1:30 to1:100.

The oltipraz crystals in the liquid compositions described abovetypically retain a MHD of from 30 to 1200 nm for at least 1 hour; moretypically the oltipraz crystals retain a MHD of from 100 to 800 nm forat least 6 hours; still more typically the oltipraz crystals retain aMHD of from 150 to 450 nm, 400 to 700 nm, 400 to 600 nm, or 450 to 550nm for at least 24 hours.

The oltipraz crystals in the solid compositions described abovetypically have a solubility in water at 20° C. of from about 3.5 toabout 8 μg/ml, more typically from about 4.5 to about 7 μg/ml, stillmore typically from about 5 to about 6.5 μg/ml.

D. Methods of Making Compositions Comprising Crystals

Methods of making compositions described herein typically provideadvantages due to their scalability. The methods described herein can beused for large, commercial-scale production (e.g., kilogram quantities),of compositions comprising the oltipraz crystals. Moreover, certainembodiments of the methods described herein can provide compositionscomprising crystals of oltipraz with a bulking agent made from aqueouscomposition using water-removal methods such as spray-drying orlyophilization. Hence, such embodiments do not generate a large amountof organic solvent waste.

Wet Milling

Oltipraz may be synthesized or may be obtained from commercial vendors,e.g. Sigma-Aldrich® and Santa Cruz Biotechnology®, Inc. Methods forsynthesizing oltipraz (4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione)have been described in the art. (See e.g. U.S. Pat. No. 4,110,450).

Wet milling of the oltipraz can be carried out by known processes. Forexample, the oltipraz can first be suspended in water to form an aqueouscomposition. A different liquid may be used in addition to, or in placeof water. The oltipraz suspension can be milled in a temperaturecontrolled grinding chamber (such as a Dyno-mill, model KDL) using agrinding media such as 0.5 mm yttrium-stabilized zirconium oxidespheres. The total grinding time is chosen so as to provide a target MHDas measured by DLS, as described above. The time for grinding varieswith the type of mill, and whether it is recirculating. While aDyno-mill may be suitable for smaller batches, other larger mills, suchas Netzsch mills, can adapt the process to much larger scales of batchesof crystals with the same target MHD. As discussed above, one or morestabilizing agents and/or surfactants may be added to the wet-millingcomposition. Where at least one stabilizing agent is provided, thecrystals may be stable in the liquid composition for a period of time.That is, the MHD of the crystals can remain within a target range for aperiod of time, e.g., at least 1 hour, 6 hours, 12 hours, 24 hours, 48hours and 72 hours. The weight percent of oltipraz in the liquid millingcomposition can vary from 1% up to 20% percent or more (excluding theweight of the milling media). Within such range are the followingsub-ranges, i.e., 1 to 5%, 5 to 10%, 5 to 15%, 10 to 15%, 10 to 20%, andmore than 20%. In certain embodiments, prior to the addition of bulkingagent, the loading of oltipraz during milling is between about 5 and 10%by weight of the aqueous composition, or about 8.6%. In otherembodiments, prior to the addition of bulking agent the loading ofoltipraz and other non-aqueous components such as the stabilizingagent(s) during milling may be between 13 and 17%, e.g., about 15%,which represents a high loading of solids for wet milling.

During milling, the temperature can be less than 40° C., but above 2° C.to avoid the composition approaching the freezing point. Generallyspeaking, however, colder is better to minimize both chemicaldegradation (to avoid drug-degradent impurities) and to lower thesolubility of the compound so the milled crystals do not grow due to adissolution/recrystallization mechanism. Using such conditions canminimize drug-degradent impurities relative to4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the aqueouscomposition to less than 1%, e.g. less than 0.5%, e.g. less than 0.1%,and minimize the drug-degradent impurities to less than 2% such as lessthan 1% or less than 0.5% relative to the4-methyl-5-(pyrazin-2-yl)-3H-1, 2-dithiole-3-thione in the aqueoussuspension. Typically, such conditions can minimize drug-degradentimpurities relative to 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the aqueous composition to less than 1%, lessthan 0.5%, or less than 0.1%, and minimize the drug-degradent impuritiesto less than 2%, less than 1% or less than 0.5% relative to the4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the aqueoussuspension. In certain embodiments, the temperature may be maintained atabout 10° C. The liquid compositions prepared from milling may be usedto prepare additional compositions, e.g., pharmaceutical compositions.Alternatively, where a dry composition of the crystals is desired, theliquid compositions may be subjected to further processing as discussedbelow to effect removal of the water and/or other solvent liquid.

Other Crystal-Formation Processes

As noted above, oltipraz crystals may be made by methods other thanmilling. For example, crystals of oltipraz may be prepared byantisolvent precipitation, supercritical fluid precipitation or otherknown means of producing compositions comprising particles having an MHDin the size ranges described herein. Stabilizing agents may be added asin the wet milling process and removal of liquids may still benecessary.

Liquid Removal

Once the target MHD of the oltipraz crystals is reached, all or aportion of the suspension then may be mixed with one or more bulkingagents as described above. The resulting mixture may be further dilutedas desired to achieve the desired target solids content prior to furtherprocessing to remove the water and/or other liquid from the composition.The final suspension may be stirred prior to the step of removing theliquid.

Where the liquid of the composition is water, known processes such asspray drying or lyophilization may be used to remove the water from thecomposition. An exemplary spray-drying process is provided below inExample 1. The resulting composition then may be further processed asdesired. The powder is preferably stable for a period of time, e.g., atleast one month, at least two months, at least three months, or at leastsix months, one year, two years, or more than two years. Stability ofthe powder may be measured at room temperature (e.g., 70° F. or 21° C.)or at a temperature below room temperature (e.g., 5° C.) or at a highertemperature and relative humidity, e.g., 40° C. and 75% RH. Stability ofthe powder may be measured according to a number of means, includingpurity, potency, or ability to re-suspend and remain substantiallyre-suspended in a liquid composition (see Example 4).

When milling and spray drying are employed in combination, the followingparameters may need to be considered and adjusted to achieve acceptableor optimal results.

Throughput: This can be an important process consideration as it candictate how high the solids loading will be during the wet milling stepand liquid removal. That is, the higher the desired throughput, thehigher the solids loading required during milling and spray-drying. Ahigh solids loading in the milling step is about 15%, although higheramounts such as about 20% may be achieved. Further, one can mill at ahigh solids loading (e.g., 15 wt %) and not dilute the aqueouscomposition with water (i.e., avoid a washing step to recover moreproduct) at any point. Then this high solids-loaded composition can befed into spray drying and sprayed at a high solids loading, e.g., about28% solids. The desire to push throughput can be dictated by the factthat the spraying is done out of water where the high dew point of waterrelative to organic solvents at similar vapor composition limits therate at which one can spray dry.

Nozzle and drying gas flow rate: In certain embodiments, spray dryingsuch solutions at high throughput can be facilitated by using atwo-fluid nozzle for atomization and adjusting the atomization gas flowrate to get the desired particle size distribution. By maintaining asufficient drying gas flow rate, the process can be relativelyinsensitive to fluctuations in solution/suspension flow rate. If theatomization gas rate is too low, however, then particle size can becomevery sensitive to suspension flow fluctuations. Running in the morerobust regime can be important because the highly viscous spraysuspension can be difficult to run at the necessary flow rate withoutsignificant fluctuations.

Time: Total residence time of the oltipraz crystals in the grindingenvironment is a parameter for milling. For a given set of millingconditions, e.g., oltipraz loading, the wet-milling machinery andmilling media used, milling temperature, and target particle size areamong the parameters that will dictate the total residence time formilling. Compositions of crystals having smaller MHD values typicallywill require longer milling times, and one of ordinary skill will beable to determine the milling time necessary for a desired MHD throughroutine experimentation.

Milling machinery and parameters: For a given target crystal size, oneof ordinary skill can find a combination of wet-milling machinery andwet-milling media that can achieve the target crystal size. For example,a target range of MHD between 150 and 600 nm, e.g., 150 to 450 nm, canbe achieved with either DynoMill or LabRAM milling machinery. For suchMHD ranges, a combination of a rotor speed for the DynoMill of about3000 rpm and 0.5 mm grinding spheres can be used. For LabRAM,acceleration of 50 g and using a combination of 0.2 mm and 0.6 mmgrinding spheres can provide acceptable results. The two systems willrequire different times however.

As noted above, in other embodiments, the crystals may be made byprecipitation, antisolvent precipitation, super critical liquidprecipitation, fluid bed granulation, wet-impregnation, evaporation(e.g., rotary evaporation, vacuum drying) and other methods known topersons of ordinary skill in the art.

E. Pharmaceutical Compositions Dry Compositions

The crystals described herein may be used to formulate various kinds ofpharmaceutical preparations. The preparations typically comprise a drycomposition as described above. Practically speaking, pharmaceuticalcompositions comprising the dry composition can comprise any amount ofthe oltipraz crystals. The amount of the composition will depend on thedesired dosage of the oltipraz and the concentration of the oltipraz inthe dry composition. In certain embodiments, for example, the drycomposition comprises a single dose of up to 5000 mg, e.g., 100 to 500mg, 500 to 1000 mg, 1000 to 1500 mg, and 1500 to 2000 mg, 2000 to 2500mg, 2500 mg to 3000 mg, 3000 mg to 4000 mg and 4000 mg to 5000 mg. Thedose may thus be from 100 to 5000 mg such as from 500 to 4000 mg, suchas from 1000 to 3000 mg e.g. from 1500 to 2000 mg. Single dosage amountsover 5000 mg also may be employed. Within such ranges are exemplaryamounts of up to 600 mg of a dry composition as described above, up to500 mg of a dry pharmaceutical composition, up to 400 mg of a drypharmaceutical composition, up to 350 mg of a dry composition, or up to300 mg of a dry composition as described herein. Exemplary amountswithin such ranges also include 250 mg, 300 mg, 350, mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg and 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600mg, 1700 mg, 1800 mg, 1900 mg and 2000 mg. As described above, such drypharmaceutical compositions can comprise from 5% to over 25% of oltiprazcrystals. For example, if the dry composition comprises 5% oltiprazcrystals, then the foregoing dosages comprise up to 250 mg of oltipraz.If the dry composition comprises 15% oltipraz crystals, then theforegoing dosages comprise up to 750 mg of oltipraz, and if the drycomposition comprises 25% oltipraz crystals, then the foregoing dosagescomprise up to 1250 mg of oltipraz.

Dry pharmaceutical compositions also may tend to be fairly electrostaticand so including a small amount of one or more pharmaceuticallyacceptable lubricants, e.g., magnesium stearate or silica oxide, canassist in the process of metering out quantities of the dry composition.Other processing techniques such as granulation, for example, rollercompaction, high shear or fluid bed, may also be used to produce largerparticles with binders or other pharmaceutical excipients that are moreeasily processed and still have rapid dissolution and greatersolubility.

Liquid Compositions

In certain embodiments, the dry composition may be re-suspended in waterand/or other liquid for oral administration as a liquid composition in aweight : weight ratio, of 1 part of dry composition and an amount ofwater of from less than 10 parts of water (or other liquid) up to 200parts or more of water (or other liquid). Within such ranges include,e.g., 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-7, 70-80, 80-90,90-100, 100-125, 125-150, 150-175, 175-200, or more than 200 parts ofwater (or other liquid) per part of dry composition. The ratio of drycomposition to liquid can therefore be from 1:10 to 1:200 such as from1:20 to 1:150 e.g. 1:30 to 1:100 such as 1:40 to 1:70 e.g. about 1:50 to1:60. As noted above, where the composition is prepared using at leastone stabilizing agent, the MHD of the crystals in the composition mayremain within the target range for a period of time, e.g., at least 1hour, at least 3 hours, at least 6 hours, at least 12 hours or at least24 hours, or longer. Further, depending on the combinations ofstabilizing agent(s), if any, and bulking agent (if any) and crystalsize, the re-suspended composition also may readily dissolve, e.g., withvigorous shaking for less than 15 minutes, less than 10 minutes, lessthan 5 minutes, less than three minutes, less than 2 minutes less thanone minute, or less than 30 seconds, and also may remain substantiallyhomogeneously suspended for a period of time, e.g., for at least 1 hour,at least 3 hours, at least 6 hours, at least 12 hours, or at least 24hours. A suspension of oltipraz crystals may be deemed to besubstantially homogeneous if the concentration of oltipraz in a testsample taken from the top of the liquid composition after a definedperiod of time (e.g., less than 1 minute, 1 minute, 2 minutes, 5minutes, 10 minutes, or 15 minutes) comprises a desired minimum targetpercentage of the original concentration, e.g., at least 85%, 90%, 95%or 98% of the concentration of oltipraz in a sample taken from theliquid composition immediately after the composition is resuspended toform a substantially homogeneous composition.

Formulations of the pharmaceutical compositions for oral administrationalso may be presented as a mouthwash, or a carbonated liquid, or an oralspray or aerosol, or an oral ointment, gel, or cream.

In certain embodiments, liquids suitable for formulating oltiprazcompositions for oral administration, e.g., buccal administration, mayinclude water; saline; buffer solutions (e.g., Krebs-Ringer Bicarbonate(KRB), citrate buffers, bicarbonate buffers, or phosphate buffers);organic solvents such as alcohols (specifically, ethanol) glycols (suchas propylene glycol, poly(ethylene glycol), butylene glycol, andglycerol (glycerin)), aliphatic alcohols (such as lanolin); mixtures ofwater and organic solvents (such as water and alcohol), and mixtures oforganic solvents such as alcohol and glycerol (optionally also withwater); lipid-based materials such as fatty acids, acylglycerols(including oils, such as mineral oil, and fats of natural or syntheticorigin), phosphoglycerides, sphingolipids and waxes; protein-basedmaterials such as collagen and gelatin; silicone-based materials (bothnon-volatile and volatile) such as cyclomethicone, dimethiconol,dimethicone, and dimethicone copolyol; hydrocarbon-based materials suchas petrolatum and squalane; polysaccharide-based materials such ascellulose, methylcellulose, and functionalized cellulose derivativessuch as hydroxypropyl methylcellulose, and other vehicles and vehiclecomponents that are suitable for administration to the oral cavity, aswell as mixtures of buccal vehicle components as identified above orotherwise known to the art.

In other embodiments, the oral formulations may be emulsions orsuspensions. For example, the formulation may be comprised of METHOCEL™and a buffer solution. METHOCEL™ refers to polymers of methylcelluloseor hydroxypropylmethyl cellulose. METHOCEL™ polymers vary in theirdegree of methoxy- and/or hydroxypropyl-substitution on the cellulosepolymeric backbone. The formulations may alternatively comprisecellulose polymers such as methylcellulose, ethylcellulose, ethylmethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethylcellulose, hydroxypropyl methylcellulose, ethylhydroxyethylcellulose, or carboxymethylcellulose. The METHOCEL™ may be present inbuffer in an amount from about 0.02 wt % to about 2 wt %. For example,the METHOCEL™ may be present in the buffer in an amount from about 0.1wt % to about 0.5wt %. METHOCEL™ can be about 0.25 wt % in buffer. TheMETHOCEL™ can be characterized by its degree of (e.g., percentage ofmonomeric units having) methoxy and/or hydroxypropyl substitution. Theformulation can also include viscosity modifiers such as a Poloxamer andalginate. Exemplary buffer solutions useful in oral formulations (e.g.,buccal formulations) include Krebs-Ringer Bicarbonate (KRB) buffer,citrate buffers, bicarbonate buffers, or phosphate buffers. In otherembodiments, the liquid may be water or saline. Typically, theconcentration of the crystals in the liquid is from about 0.004% toabout 0.4%, such as from about 0.010% to about 0.040%, e.g. about 0.012%by weight of the liquid formulation. In certain embodiments, theconcentration of the crystals in the liquid is about 0.004% to about0.4%, 0.010% to about 0.040%, or 0.012% by weight of the liquidformulation. The concentration may also be represented by the percentageby weight of the crystals in the liquid formulation. Typically, thecrystals are present in an amount of from about 0.026% to about 2.6%,e.g. from about 0.04% to about 0.4%, such as about 0.078% by weight ofthe formulation. In certain such embodiments, the crystals are presentin about 0.026% to about 2.6%, 0.04% to about 0.4%, or about 0.078% byweight of the formulation. Other polymeric thickeners such as PVP orPVP/VA 64 may also be used.

Liquid dosage forms useful for oral administration includepharmaceutically acceptable emulsions, microemulsions, suspensions,syrups and elixirs. In addition to the active ingredient, the liquiddosage forms may contain inert diluents commonly used in the art, suchas, for example, water or other solvents, cyclodextrins and derivativesthereof, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of this disclosure includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired crystal size in the case of dispersions, and by the use ofsurfactants.

Compositions for oral administration may include additional components,such as coloring agents, flavoring agents, fragrances, antimicrobialagents, or sweetening agents as further described.

Alternative embodiments of pharmaceutical compositions suitable for oraladministration include compositions in the form of capsules (includingsprinkle capsules and gelatin capsules), sachets, stickpacks, pills,tablets, lozenges (using a flavored basis, usually sucrose and acacia ortragacanth), lyophile, powders, granules, implantable compositions, oras a solution or a suspension in an aqueous or non-aqueous liquid,including, e.g., compositions suitable for injection or infusion, or asan oil-in-water or water-in-oil liquid emulsion, or as an elixir orsyrup, or as pastilles (using an inert base, such as gelatin andglycerin, or sucrose and acacia) and/or as mouth washes and the like,each containing a predetermined amount of a composition comprising aquantity of crystals as described herein as the active ingredient.Compositions or compounds may also be administered as a bolus, electuaryor paste.

To prepare solid dosage forms for oral administration (capsules(including sprinkle capsules and gelatin capsules), tablets, pills,dragees, powders, granules and the like), a composition comprising aquantity of the oltipraz crystals, e.g., a dry composition as describedabove, can be mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: (1) fillers or extenders, such as starches,microcrystalline cellulose, maltodextrins, lactose, sucrose, glucose,mannitol, and/or silicic acid; (2) binders, such as, for example,hydroxypropyl cellulose, hydroxypropylmethyl cellulose,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as sodium carboxymethylcellulose, sodiumstarch glycolate, crospovidone, agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, cetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, sodium stearyl fumarate,silica oxide, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; (10) complexing agents, such as, modified andunmodified cyclodextrins; and (11) coloring agents. In the case ofcapsules (including sprinkle capsules and gelatin capsules), tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin, PVP, or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions, such as dragees, capsules (including sprinkle capsules andgelatin capsules), pills and granules, may optionally be scored orprepared with coatings and shells, such as enteric coatings and othercoatings well known in the pharmaceutical-formulating art. They may alsobe formulated so as to provide slow or controlled release of the activeingredient therein using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile, otherpolymer matrices, liposomes and/or microspheres. They may be sterilizedby, for example, filtration through a bacteria-retaining filter, or byincorporating sterilizing agents in the form of sterile solidcompositions that can be dissolved in sterile water, or some othersterile injectable medium immediately before use. These compositions mayalso optionally contain opacifying agents and may be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain portion of the gastrointestinal tract, optionally, in a delayedmanner. Examples of embedding compositions that can be used includepolymeric substances and waxes. The active ingredient can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

The composition may further include components adapted to improve thestability or effectiveness of the applied formulation. Suitablepreservatives include, but are not limited to: ureas, such asimidazolidinyl urea and diazolidinyl urea; chlorphenesin;methylisothiazolinone; phenoxyethanol; sodium methyl paraben,methylparaben, ethylparaben, and propylparaben; ethylhexyl glycerin;potassium sorbate; sodium benzoate; sorbic acid; benzoic acid; caprylylglycol; formaldehyde; phytosphingosine; citric acid; sodium citrate;zinc citrate; chlorine dioxide; quaternary ammonium compounds, such asbenzalkonium chloride, benzethonium chloride, cetrimide, dequaliniumchloride, and cetylpyridinium chloride; mercurial agents, such asphenylmercuric nitrate, phenylmercuric acetate, and thimerosal;piroctone olamine; Vitis vinifera seed oil; and alcoholic agents, forexample, chlorobutanol, dichlorobenzyl alcohol, phenylethyl alcohol, andbenzyl alcohol.

Suitable antioxidants include, but are not limited to, ascorbic acid andits esters, sodium bisulfite, butylated hydroxytoluene, butylatedhydroxyanisole, tocopherols (such as α-tocopherol), tocopheryl acetate,superoxide dismutase, oxidoreductases, Arabidopsis thaliana extract,chrysin, black raspberry seed oil, raspberry seed oil, pomegranate seedoil, cranberry seed oil, sodium ascorbate/ascorbic acid, ascorbylpalmitate, propyl gallate, and chelating agents like EDTA (e.g.,disodium EDTA), citric acid, and sodium citrate.

In addition, combinations or mixtures of preservatives or anti-oxidantsmay also be used.

Suitable buffer salts also may be added. Examples include, but are notlimited to sodium citrate, citric acid, sodium phosphate monobasic,sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphatemonobasic, potassium phosphate dibasic, and potassium phosphatetribasic.

Suitable viscosity adjusting agents (i.e., thickening and thinningagents or viscosity modifying agents) also may be added and include, butare not limited to, protective colloids or non-ionic gums such ashydroxyethylcellulose, xanthan gum, and sclerotium gum, as well asmagnesium aluminum silicate, silica, microcrystalline wax, beeswax,paraffin, and cetyl palmitate. Cross-polymers of acrylates/C₁₀₋₃₀ alkylacrylate are also considered. In addition, appropriate combinations ormixtures of these viscosity adjusters may be utilized.

Additional constituents include, but are not limited to: epitheliumprotectants, adsorbents, anti-oxidants, coating agents, coloring agents,demulcents, emollients, moisturizers, sustained release materials,solubilizing agents, epithelium-penetration agents, soothing agents,vitamins, anti-irritants, absorbents, anti-caking agents, anti-staticagents, astringents (e.g., witch hazel, alcohol, and herbal extractssuch as chamomile extract), binders/excipients, buffering agents,chelating agents, film forming agents, conditioning agents, opacifyingagents, lipids, immunomodulators, sweeteners, flavoring agents,perfuming agents, antimicrobial agents and pH adjusters (e.g., citricacid, sodium hydroxide, and sodium phosphate).

For example, lipids normally found in healthy epithelium (or theirfunctional equivalents) may be incorporated into emulsions. In certainembodiments, the lipid is selected from the group consisting ofceramides, cholesterol, and free fatty acids. Examples of lipidsinclude, but are not limited to, ceramide 1, ceramide 2, ceramide 3,ceramide 4, ceramide 5, ceramide 6, hydroxypropyl bispalmitamide MEA,and hydroxypropyl bislauramide MEA, and combinations thereof.

Examples of peptides that interact with protein structures of thedermal-epidermal junction include palmitoyl dipeptide-5 diaminobutyloylhydroxythreonine, palmitoyl tripeptide-5, acetyl octapeptide-3,pentapeptide-3, palmitoyl dipeptide-5 diaminohydroxybutyrate, dipeptidediaminobutyroyl benzylamide diacetate, palmitoyl tetrapeptide-7,palmitoyl oligopeptide, and palmitoyl dipeptide-6diaminohydroxybutyrate.

Examples of epithelium soothing agents include, but are not limited toalgae extract, mugwort extract, stearyl glycyrrhetinate, bisabolol,allantoin, aloe, avocado oil, green tea extract, hops extract, chamomileextract, colloidal oatmeal, calamine, cucumber extract, and combinationsthereof.

Examples of vitamins include, but are not limited to, vitamins A, B, B5,D, E, K, and combinations thereof. Vitamin analogues are alsocontemplated; for example, the vitamin D analogues calcipotriene orcalcipotriol.

Suitable fragrances, flavors, sweetening agents, and colors may be usedin the compositions described herein. Examples of sweetening agentsinclude sucrose or saccharin; Examples of flavoring agents includepeppermint, methyl salicylate, or orange flavoring. Further examples offragrances, flavors, and colors suitable for use in buccal products areknown in the art.

One or more additional agents that are generally recognized as safe foradministration to humans and can be co-administered together with theoltipraz composition, or co-administered separately as part of a dosingregimen with the oltipraz composition, include N acetylcysteine and/orother antioxidants, BHT, pantothenic acid (vitamin B5) or other agentsthat enhance glutathione synthesis, glutathione, e.g., for topicaladministration, Medihoney (for topical administration), curcumin (fortopical administration) or other NF-kappaB inhibitors, Mesalamine and/orother anti-inflammatory agents, e.g., for oral or rectal administrationcompositions, and superoxide dismutase or other compounds that preventdamage from reactive O₂ ⁻ (superoxide).

Devices for Oral Administration

In certain embodiments, liquid formulations for oral administration maybe prepared and administered using a device that facilitatesadministration of a single dose of the pharmaceutical composition. Suchdevices, which are known in the art, can include a cavity or reservoirwhere a dry composition and a liquid such as water and/or a non-aqueoussolvent may be mixed and then administered to the patient via an openingin the device. Typically, such devices comprise a compartment, separatefrom the cavity, where a dry powder can reside. At the time ofadministration, the powder is released from the compartment into thecavity or reservoir, and in some embodiments, by breaking a barrier thatseparates the compartment from the cavity or reservoir. Thereafter, thepowder may be mixed, typically by shaking, with a liquid in the cavitythat may have been added earlier or at the time. The cavity is ofsufficient size to hold both the dry pharmaceutical composition and aquantity of liquid comprising an amount of water and/or non-aqueoussolvent sufficient to permit mixing of the dry pharmaceuticalcomposition to form a liquid composition. The liquid may be added to thecontainer at the time of packaging to create a self-contained productcomprising both dry composition and liquid that may be mixed together atthe time of administration. Alternatively, the container can containonly a dry pharmaceutical composition and the liquid is then added priorto administration. The liquid may contain flavoring additives asdiscussed below. Alternatively, the powder and the liquid can be sealedin 2 form-fill-and-seal pouches, either side by side or one on top ofthe other and separated by a rupturable seal. The person administeringthe drug would then rupture the seal and mix the contents back and forthbetween the 2 compartments until dissolved..

Once the composition is substantially homogeneous (e.g., from theshaking), it is then administered to the patient via an opening in thedevice created, e.g., by uncoupling a portion of the device to exposethe cavity containing the liquid mixture. For example, a portion of thedevice, e.g., the top, can be removed by unscrewing a threaded portionfrom another threaded portion of the container to expose the cavitycontaining the liquid mixture, which then may be administered to thepatient or by the patient. Examples of such devices are provided in U.S.Pat. No. 6,148,996, U.S. application No. 20080202949, and U.S. Pat. No.3,156,369. Such single-use devices can be employed for orallyadministering liquid compositions described herein, especially forprophylaxis or treatment of oral mucositis or its symptoms as describedbelow.

The disclosure thus also provides a kit comprising (i) oltipraz crystalsor a composition comprising oltipraz crystals as described herein and(ii) a device for oral administration of such crystals or compositions.The kit optionally further contains instructions for use.

Compositions for Topical Administration

In some embodiments, the formulations may be suitable for topicaladministration, and may include any of the constituents outlined below.

Suitable moisturizers for use in the formulations include, but are notlimited to, lactic acid and other hydroxy acids and their salts,glycerol, propylene glycol, butylene glycol, sodium PCA, sodiumhyaluronate, Carbowax 200, Carbowax 400, and Carbowax 800.

Suitable humectants include, but are not limited to, panthenol, cetylpalmitate, glycerol (glycerin), PPG-15 stearyl ether, lanolin alcohol,lanolin, lanolin derivatives, cholesterol, petrolatum, isostearylneopentanoate, octyl stearate, mineral oil, isocetyl stearate, myristylmyristate, octyl dodecanol, 2-ethylhexyl palmitate (octyl palmitate),dimethicone, phenyl trimethicone, cyclomethicone, C₁₂-C₁₅ alkylbenzoates, dimethiconol, propylene glycol, Theobroma grandiflorum seedbutter, sunflower seed oil, ceramides (e.g., ceramide 2 or ceramide 3),hydroxypropyl bispalmitamide MEA, hydroxypropyl bislauramide MEA,hydroxypropyl bisisostearamide MEA,1,3-bis(N-2-(hydroxyethyl)stearoylamino)-2-hydroxy propane,bis-hydroxyethyl tocopheryl-succinoylamido hydroxypropane, urea, aloe,allantoin, glycyrrhetinic acid, safflower oil, oleyl alcohol, oleicacid, stearic acid, dicaprylate/dicaprate, diethyl sebacate, isostearylalcohol, pentylene glycol, isononyl isononanoate, polyquaternium-10(quaternized hydroxyethyl cellulose), camellia oleifera leaf extract,phytosteryl canola glycerides, shea butter, caprylic/caprictriglycerides, punica granatum sterols, ethylhexyl stearate, betaine,behenyl alcohol (docosanol), stearyl alcohol (1-octadecanol), laminariaochroleuca extract, behenic acid, caproyl sphingosine, caproylphytosphingosine, dimethicone-divinyldimethicone-silsesquioxanecrosspolymer, potassium lactate, sodium hyaluronate crosspolymer,hydrolyzed hyaluronic acid, sodium butyroyl-formoyl hyaluronate,polyglutamic acid, tetradecyl aminobutyroylvalylaminobutyric ureatrifluoroacetate, micrococcus lysate, hydrolyzed rice bran protein,glycine soja protein, and 1,3-bis(N-2-(hydroxyethyl)palmitoylamino)-2-hydroxypropane.

The topical compositions also may be delivered transdermally via a patchthat is applied over the skin, and such patches are well known in theart.

Persons of skill in the art will recognize other topical deliverycompositions and vehicles that may be used.

Compositions for Rectal/Colonic Delivery

In certain embodiments, the pharmaceutical compositions can beformulated for rectal administration to provide colon-specific deliveryusing known methods and compositions. Generally speaking, delivery ofpharmaceutical composition via rectal administration route can beachieved by using suppositories, enemas, ointments, creams or foams.Suppositories are among the most common rectal dosage forms, and basesare generally fatty in nature, but water-soluble or water-miscible basescan also be utilized. In order to achieve a desirable bioavailabilitythe active ingredient should come in contact with the rectal or colonicmucosa.

Suitable excipients for preparing compositions for rectal administrationsuch as, but not limited to, vehicle, preservatives, surfactants,emulsifiers, mineral oils, propellants, thickening agents, lubricants,preservatives, pH adjusting agents, chelating agents, emollients and/orhumectants, permeation enhancers, suspension-forming agents ormucoadhesive agents or combinations thereof. The vehicle may include anaqueous, non-aqueous or a hydro-alcoholic vehicle. Suitable aqueousvehicles which are compatible with the rectal and colonic mucosa, maycomprise water soluble alkanols selected from, but not limited to,ethanol, polyalcohols such as a propylene glycol, glycerol,polyethyleneglycol, polypropylene glycol, propylene glycol glycerylesters and combinations thereof. Non-aqueous vehicles which may beemployed in pharmaceutical rectal foam compositions, including but notlimited to vegetable oils, such as olive oil; injectable organic esters,such as ethyl oleate and combinations thereof.

Suitable surfactants that may be employed in pharmaceutical compositionsfor rectal administration, e.g. anionic surfactants, non-ionicsurfactants, cationic surfactants, and amphoteric (zwitterionic)surfactants. Anionic surfactants may include, but are not limited to,ammonium lauryl sulfate, sodium lauryl sulfate, ammonium laurethsulfate, sodium laureth sulfate, alkyl glyceryl ether sulfonate,triethylamine lauryl sulfate, triethylamine laureth sulfate,triethanolamine lauryl sulfate, triethanolamine laureth sulfate,monoethanolamine lauryl sulfate, monoethanolamine laureth sulfate,diethanolamine lauryl sulfate, diethanolamine laureth sulfate, lauricmonoglyceride sodium sulfate, potassium lauryl sulfate, potassiumlaureth sulfate, sodium lauryl sarcosinate, sodium lauroyl sarcosinate,lauryl sarcosine, cocoyl sarcosine, ammonium cocoyl sulfate, ammoniumlauroyl sulfate, sodium cocoyl sulfate, sodium lauroyl sulfate,potassium cocoyl sulfate, potassium lauryl sulfate, triethanolaminelauryl sulfate, triethanolamine lauryl sulfate, monoethanolamine cocoylsulfate, monoethanolamine lauryl sulfate, sodium tridecyl benzenesulfonate, sodium dodecyl benzene sulfonate, sodium and ammonium saltsof coconut alkyl triethylene glycol ether sulfate; tallow alkyltriethylene glycol ether sulfate, tallow alkyl hexaoxyethylene sulfate,disodium N-octadecylsulfosuccinate, disodium lauryl sulfosuccinate,diammonium lauryl sulfosuccinate, tetrasodium N-(1 ,2-dicarboxyethyl)-N-octadecylsulfosuccinate, diamyl ester of sodium sulfosuccinic acid,dihexyl ester of sodium sulfosuccinic acid, dioctyl esters of sodiumsulfosuccinic acid, docusate sodium, and combinations thereof.

Nonionic surfactants may include, but are not limited to,polyoxyethylene fatty acid esters, sorbitan esters, cetyl octanoate,cocamide DEA, cocamide MEA, cocamido propyl dimethyl amine oxide,coconut fatty acid diethanol amide, coconut fatty acid monoethanolamide, diglyceryl diisostearate, diglyceryl monoisostearate, diglycerylmonolaurate, diglyceryl monooleate, ethylene glycol distearate, ethyleneglycol monostearate, ethoxylated castor oil, glyceryl monoisostearate,glyceryl monolaurate, glyceryl monomyristate, glyceryl monooleate,glyceryl monostearate, glyceryl tricaprylate/caprate, glyceryltriisostearate, glyceryl trioleate, glycol distearate, glycolmonostearate, isooctyl stearate, lauramide DEA, lauric acid diethanolamide, lauric acid monoethanol amide, lauric/myristic acid diethanolamide, lauryl dimethyl amine oxide, lauryl/myristyl amide DEA,lauryl/myristyl dimethyl amine oxide, methyl gluceth, methyl glucosesesquistearate, oleamide DEA, PEG-distearate, polyoxyethylene butylether, polyoxyethylene cetyl ether, polyoxyethylene lauryl amine,polyoxyethylene lauryl ester, polyoxyethylene lauryl ether,polyoxyethylene nonylphenyl ether, polyoxyethylene octyl ether,polyoxyethylene octylphenyl ether, polyoxyethylene oleyl amine,polyoxyethylene oleyl cetyl ether, polyoxyethylene oleyl ester,polyoxyethylene oleyl ether, polyoxyethylene stearyl amine,polyoxyethylene stearyl ester, polyoxyethylene stearyl ether,polyoxyethylene tallow amine, polyoxyethylene tridecyl ether, propyleneglycol monostearate, sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitantrioleate, stearamide DEA, stearic acid diethanol amide, stearic acidmonoethanol amide, laureth-4, and combinations thereof.

Amphoteric surfactants may include, but are not limited to, sodiumN-dodecyl-beta-alanine, sodium N-lauryl-beta-iminodipropionate,myristoamphoacetate, lauryl betaine, lauryl sulfobetaine, sodium3-dodecyl-aminopropionate, sodium 3-dodecylaminopropane sulfonate,sodium lauroamphoacetate, cocodimethyl carboxymethyl betaine,cocoamidopropyl betaine, cocobetaine, lauryl amidopropyl betaine, oleylbetaine, lauryl dimethyl carboxymethyl betaine, lauryl dimethylalphacarboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, laurylbis-(2-hydroxyethyl) carboxymethyl betaine, stearylbis-(2-hydroxypropyl)carboxymethyl betaine, oleyl dimethylgamma-carboxypropyl betaine, laurylbis-(2-hydroxypropyl)alpha-carboxyethyl betaine, oleamidopropyl betaine,coco dimethyl sulfopropyl betaine, stearyl dimethyl sulfopropyl betaine,lauryl dimethyl sulfoethyl betaine, laurylbis-(2-hydroxyethyl)sulfopropyl betaine, and combinations thereof.

Cationic surfactants may include, but are not limited to, behenyltrimethyl ammonium chloride, bis(acyloxyethyl)hydroxyethyl methylammonium methosulfate, cetrimonium bromide, cetrimonium chloride, cetyltrimethyl ammonium chloride, cocamido propylamine oxide, distearyldimethyl ammonium chloride, ditallowedimonium chloride, guarhydroxypropyltrimonium chloride, lauralkonium chloride, lauryldimethylamine oxide, lauryl dimethylbenzyl ammonium chloride, laurylpolyoxyethylene dimethylamine oxide, lauryl trimethyl ammonium chloride,lautrimonium chloride, methyl- 1 -oleyl amide ethyl-2-oleylimidazolinium methyl sulfate, picolin benzyl ammonium chloride,polyquatemium, stearalkonium chloride, stearyl dimethylbenzyl ammoniumchloride, stearyl trimethyl ammonium chloride, trimethylglycine, andcombinations thereof.

Suitable thickening agents or viscosity modifying agents which may beemployed in the pharmaceutica composition for rectal administrationinclude, but are not limited to, carboxymethyl cellulose,polyoxyethylene-polyoxypropylene copolymers, xanthan gum, agar, guargum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl celluloseand combinations thereof.

Alternatively, colonic absorption can be accomplished through oraladministration of compositions designed to release the active oltiprazin the colon. Such compositions can be in an oral dosage form, e.g., apill or capsule, that provides delayed release until the dosage form isin the colon

Compositions and Devices for Inhalation Administration

In other embodiments, oltipraz-containing compositions may be deliveredvia the respiratory tract by providing the composition in inhalableform, e.g., in an inhaler device, either in dry powder form or in aliquid carrier. For example, inhalable compositions can comprise theactive ingredient in dry powder compositions provided in dry powderinhalers. See, e.g., WO2014177519 and US20140065219. Alternatively,inhalable compositions can comprise the active ingredient in a liquidcarrier such as ethanol. See, e.g., EP2536412 A2.

The disclosure thus also provides a kit comprising (i) oltipraz crystalsor a composition comprising oltipraz crystals as described herein and(ii) a device for administering such crystals or compositions byinhalation. The kit optionally further contains instructions for use.

F. Methods of Treating

In certain embodiments, the pharmaceutical compositions may be used fortreating a human or non-human animal patient in need. The patienttypically will be a human patient, although the pharmaceuticalcompositions of this disclosure can be used for treating non-humananimals, e.g., for veterinary uses. The compositions of this disclosuremay be used for preventing or treating a wide variety of diseases andconditions, including diseases and conditions for which treatment witholtipraz is known. Examples of such diseases and conditions includemucositis, HIV, cancers, hepatitis (including HBV and HCV),keratin-based skin diseases, including skin blistering and epidermolysisbullosa simplex and related diseases, inflammatory disorder or disease(including endothelial dysfunction and cardiovascular disease), sepsis,contrast-induced nephropathy, diabetes, obesity, PCOS, steatosis,hyperlipidemia, and hypertension, chronic kidney disease, pulmonaryfibrosis, hypoxic conditions, chemical-induced lung injury, respiratorydistress disorder, anon gap acidosis, nephritis, lupus, interstitiallung disease, graft dysfunction, hepatitis, acute kidney injury,noise-induced hearing injuries, poison ingestion, retinopathy,neurotoxicity, cancer-induced injury such as ototoxicity, respiratoryinfections, autism, conditions involving vasospasm, and conditionsconsidered treatable by provision of n-acetylcysteine, injectablereduced glutathione, or a known intracellular glutathione enhancingagent.

Typically, the composition is provided to the patient in an effectiveamount. The term “effective amount” is used herein to refer to an amountof the therapeutic composition sufficient to produce a significantbiological response (e.g., a significant decrease in inflammation).Actual dosage levels of the oltipraz in a therapeutic composition can bevaried so as to administer an amount that is effective to achieve thedesired therapeutic response for a particular subject and/orapplication. Of course, the effective amount in any particular case willdepend upon a variety of factors including formulation, route ofadministration, combination with other drugs or treatments, severity ofthe condition being treated, and the physical condition and priormedical history of the subject being treated.

As used herein, the term “subject” includes both human and animalsubjects, and thus veterinary therapeutic uses are provided inaccordance with this disclosure. The terms “treatment” or “treating”relate to any treatment of a condition of interest (e.g., mucositis, aninflammatory disorder or a cancer), including but not limited toprophylactic treatment and therapeutic treatment. As such, the terms“treatment” or “treating” include, but are not limited to: preventing acondition of interest or the development of a condition of interest;inhibiting the progression of a condition of interest; arresting orpreventing the further development of a condition of interest; reducingthe severity of a condition of interest; ameliorating or relievingsymptoms associated with a condition of interest; and causing aregression of a condition of interest or one or more of the symptomsassociated with a condition of interest.

The compositions are suitable for treating patients who are sufferingfrom mucositis, e.g., in the oral cavity (including in the buccalcavity), in the alimentary canal, in the colon and/or rectum, and/or onthe skin. Such patients, e.g., may be undergoing chemotherapy and/orradiation therapy, e.g., radiation treatment in the head and neck area,or to another area of the body. Such compositions may be used toaccomplish one, more than one, or all of the following beneficialeffects on human or non-human animal patients, i.e., (i)prophylactically prevent or delay the onset of mucositis, including oralmucositis (e.g., inflammation of the mucosa), (ii) treat existingmucositis, including oral mucositis (iii) alleviate symptoms associatedwith mucositis, including oral mucositis (iv) reduce or lessen theseverity of existing mucositis, including oral mucositis (v) hasten thecure or healing of mucositis, including oral mucositis (vi) reduce theincidence and/or duration of mucositis, including oral mucositis, e.g.,mild, moderate and severe oral mucositis, (vii) prophylactically preventor delay the onset of weight loss by a patient with oral mucositis,(viii) lessen the amount of weight loss experienced by a patient withoral mucositis, and/or (ix) increase the ability of a patient with oralmucositis to take food by mouth. Such compositions also may be used forthe prevention and/or treatment of patients with dysphagia (difficultyswallowing), e.g., cancer patients, or to delay the onset of dysphagiaor lessen the severity of dysphagia, e.g., in cancer patients. Suchcompositions also may be used for the prevention and/or treatment ofpatients with xerostomia (the subjective feeling of oral dryness), or todelay the onset of xerostomia, lessen the severity of xerostomia, and/orreduce the incidence of moderate-to-severe xerostomia. In certainembodiments, the single-use devices described above may be used foradministration of liquid compositions for accomplishing one, more thanone, or all of the above relating to oral mucositis, dysphagia andxerostomia. Advantageously, formulations are also non-irritating,well-tolerated, palatable (if orally administered), non-cytotoxic,weakly or non-sensitizing, non-sensitizing.

Certain embodiments herein provide methods for treating mucositis,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a composition as described herein. The disclosurealso provides a composition as described herein for use in the treatmentof mucositis. The disclosure also provides the use of a composition asdescribed herein in the manufacture of a medicament for the treatment ofmucositis. The administration of the formulation to a patient may be anoral administration, including buccal administration. The methods ofadministration described herein can represent a treatment regimen of apredetermined duration, e.g., 1 month, 2 months, 3 months, 4 months, 5months, 6 months, or longer. Compositions according to this disclosurecan be applied or administered once daily, twice daily, three timesdaily, or as needed. In situations where the patient is undergoingchemotherapy and or radiation therapy, the dosage may be administeredprior to a treatment, e.g., within 1 hour, within 3 hours, within 6hours, within 12 hours, within 24 hours, or more than 24 hours beforethe treatment. Additionally, or alternatively, the dosage may beadministered after a treatment, e.g., within 1 hour, within 3 hours,within 6 hours, within 12 hours, within 24 hours after the treatment, ormore than 24 hours after the treatment.

Where liquid compositions are administered, the composition may beadministered orally or parenterally, e.g., by subcutaneous,intramuscular, intrasternal, or intravenous injection. Where oraladministration is employed, the liquid composition simply may beswallowed, or it may be administered by a “swish and swallow” regimen ora “swish and spit” regimen. By administering the composition orally in aliquid form to a patient with oral mucositis, the compositions mayprovide a therapeutic dosage of oltipraz at the site of administration,which can provide a therapeutic benefit in terms of the mucositis asdescribed above, i.e., it may prophylactically prevent the onset ofmucositis, treat existing mucositis, alleviate symptoms associated withmucositis (e.g., inflammation of the mucosa), reduce or lessen theseverity of existing mucositis, and/or hasten the cure or healing ofmucositis. In such cases, liquid compositions comprising an ingredientwith a negative charge, e.g., a cationic surfactant or polymer such asEudragit RL, may provide a further advantage by virtue of providing anadherence or association with the mucosa of the mouth, which tends tohave a positive charge. The physical and chemical properties ofembodiments of the compositions described herein can impartcharacteristics to the formulation such as stability, delivery of theactive agent to the mucosal membrane, and ease of administration.

As noted above, oltipraz compositions as described herein may beco-administered with other therapeutic agents, either together orseparately as part of a therapeutic regimen. Such agents include Nacetylcysteine and/or other antioxidants, pantothenic acid (vitamin B5)or other agents that enhance glutathione synthesis, glutathione, e.g.,for topical administration, Medihoney (for topical administration),curcumin (for topical administration) or other NF-kappaB inhibitors,Mesalamine and/or other anti-inflammatory agents, e.g., for oral orrectal administration compositions, and superoxide dismutase or othercompounds that prevent damage from reactive O₂ ⁻ (superoxide).

EXAMPLES

Certain embodiments of this disclosure are further illustrated by thefollowing examples, which should not be construed as limiting in anyway.

Example 1: Method for Manufacturing an Oltipraz Composition

A pharmaceutical composition comprising oltipraz, stabilizing agentspolysorbate 80 and Eudragit RL, and a bulking polymer,polyvinylpyrrolidone vinylacetate (PVP-VA64), was manufactured by thefollowing steps.

In an appropriate sized container with agitator, formulation componentswere added in the following order: stabilizing polymer, purified water,polysorbate 80, then oltipraz. The mixture was stirred to create ahomogeneous suspension vehicle. The composition of the suspensionvehicle prior to milling is shown in Table 2. The suspension vehicle wasmilled in a temperature controlled grinding chamber (such as aDyno-mill, model KDL) with 0.5 mm yttrium-stabilized zirconium oxidespheres as a grinding media. A list of additional mill parameters isshown in Table 3. Total milling time of the suspension was 270 minutes,determined based on a target mean residence time of 7 minutes in thegrinding chamber (see Equation 1). The MHD of the crystals/particles inthe milled suspension was measured by dynamic light scattering (DLS)performed as described above and was 330 nm.

The milled suspension was transferred to a new, appropriate sizedsolution tank, bulking polymer PVP-VA64 was added, and then additionalpurified water to dilute the suspension to 28% total solids. The finalsuspension composition shown in Table 4 was then stirred for at least 30minutes. The suspension was spray dried with a Niro PSD-1 spray dryerusing parameters shown in Table 5. Spray dried powder was collected in acyclone.

TABLE 2 Composition of Suspension Vehicle Composition (weight ComponentFunction percent of suspension) Eudragit RL Stabilizing agent 4.3Polysorbate 80 Stabilizing agent 2.1 Oltipraz Active 8.6 Water, USPPurified Solvent 85.0

TABLE 3 Parameters Used with the Dyno-mill KDL Parameter Value Chambersize 0.6 L Agitator Paddles 64 mm Gap size 0.2 mm Rotor SpeedApproximately 3000 rpm (belt position 3) Mill mode Continuous Grindingmedia volume 2000 g Suspension Temperature (Reservoir) 2.0-40.0° C.Suspension Temperature (Mill outlet) 2.0-40.0° C. Suspension Flow Rate500 mL/min Mill Run Time 270-300 minutes

Example Calculation for Total Required Milling Time of SuspensionVehicle

${\frac{{Working}\mspace{14mu} {chamber}\mspace{14mu} {volume}}{F}*{total}\mspace{14mu} {mill}\mspace{14mu} {time}} = {7\mspace{14mu} {minutes}}$${{where}\mspace{14mu} F} = \frac{{total}\mspace{14mu} {suspension}\mspace{14mu} {mass}}{{suspension}\mspace{14mu} {density}}$

Working chamber volume was defined as the empty chamber volume minus thevolume of the grinding media.

TABLE 4 Composition of Spray Suspension Composition (% of ComponentFunction suspension) Milled Suspension (from Table 1) — 48.7 PVP-VA 64Bulking 20.7 polymer Water, USP Purified Solvent 30.6

TABLE 5 Spray Drying Process Conditions on a PSD-1 Scale Spray DryerProcess Condition Value Atomizer Spray Systems 2-fluid 2850/120Atomization gas pressure (psig) 20 Drying-gas inlet temperature (° C.)105 Drying-gas outlet temperature (° C.) 50 Solution flow rate (g/min)35 Drying-gas flow rate (g/min) 1850

The spray dried powder was analyzed to confirm the powder re-suspendedin water within 2 minutes, and the resulting oltipraz milled crystalsize was similar to the original crystal size achieved during themilling step. Two tests were performed: first, the powder wasre-suspended in water at an oltipraz concentration of 5 mg/mL and thetime to uniform suspension by visual observation was recorded. Second,the resulting crystal size of the suspension was measured by DLS. Thespray dried powder re-suspended in water with vigorous shaking within 2minutes, and the resulting suspension crystal size was 370 nm which wassimilar to the original milled suspension crystal size.

Example 2: Stability Testing of an Oltipraz Composition

Samples of a lot of a dry oltipraz composition similar to that preparedin Example 1 were subjected to stability testing for three months at 5°C., 25° C. and 60% relative humidity (RH), and 40° C. and 75% RH. Thesamples (10 g) were contained inside an LDPE (low density polyethylene)pouch, which was subsequently placed inside of a foil bag. Desiccant (1g) was put in the foil bag, and then the foil bag was hermetically heatsealed. Results were as follows:

-   -   Powder is still same intense orange.    -   Flowability was poor due to static, as expected. There is no        clumping at any condition.    -   Re-suspension was performed at 5 mg/mL. It was very fast in that        the powder re-suspended fully in less than 15 sec of shaking.    -   DLS performed immediately after re-suspension showed particle        size of re-suspended crystals remained less than 600 nm (see        Table 6 below).    -   At 3-month time point, 24 hour stability of suspension was        tested. After initial test, suspension was left on counter 24        hours. Minor settling occurred during that time, but a 15 second        shake re-suspended all. DLS showed particle size had not        changed.    -   Potency results were as expected, within error.    -   Glass transition temperature and crystalline melt temperature of        the spray dried crystals were unchanged at 3-months.

TABLE 6 Z-Average Particle Size (nm) by Intensity of Oltipraz CrystalSuspension in Water (average of n = 2) 1 3 3 Month + Condition t = 0Month Month 1 day suspended  5° C. 370 422 377 299 25° C. and 60% RH 370412 325 302 40° C. and 75% RH 370 393 324 314

FIG. 3a is a SEM image at 5000× magnification of the dry compositioncomprising oltipraz at t=0. FIG. 3b is a SEM image at 5000×magnification of the dry composition after stability testing for threemonths at 40° C. and 75% RH. FIG. 3c is a SEM image at 1500×magnification of the dry composition after stability testing for threemonths at 40° C. and 75% RH. As can be seen from the figures, particlemorphology did not change over time under the test conditions. Theparticles are still raisin-like to spherical particles with no evidenceof crystal growth or particle fusing.

Example 3: Study for the Assessment of Oltipraz Composition for theTreatment of Oral Mucositis Induced by Acute Radiation in Hamsters

Twenty-four (24) male Syrian Golden Hamsters were used in the study.Mucositis was induced by giving an acute radiation dose of 40 Gydirected to the left buccal cheek pouch on Day 0. Mucositis wasevaluated clinically starting on Day 6, and continuing on alternate daysuntil Day 28. Placebo, recrystallized (neat) oltipraz, or a formulatedoltipraz composition (described below) at a concentration of 5 mg/mL(based on the amount of crystals in the suspension) was administered bytopical application of 0.2 mL directed to the left cheek pouch, twicedaily (BID; 1 mg/dose; 2 mg/day) from Days -3 (first dose prior toirradiation) to Day 28.

The formulated oltipraz composition was prepared generally according tothe process described in Example 1 and contained 16.7% wt/wt ofnanomilled oltipraz crystals (MHD<350 nm) that has been formulated withEudragit RL, Tween 80 and PVP-VA64 and spray-dried The neat oltipraz wasrecrystallized oltipraz prepared according to the process disclosed inWO2016207914.

Results and Conclusions

-   -   There were no animal deaths at any time during this study.    -   There were no significant differences in overall mean percent        weight change between the placebo control group and the        treatment groups from Day −3 to 28, although animals dosed with        the formulated oltipraz composition gained substantially more        weight and at a significantly faster rate than the animals that        were administered neat oltipraz (FIG. 4A), indicating a        biological difference in the level of activity.    -   The maximum mean mucositis score observed in the placebo group        was 3.13±0.09 and occurred on Day 16. Animals dosed with neat        oltipraz (Group 2) experienced peak mean mucositis score on Day        16 at 3.25±0.11. Animals dosed with the formulated oltipraz        composition (Group 3) experienced peak mean mucositis score of        2.63±0.13 and first occurred on Day 14.    -   Mean daily blind mucositis scores are shown in FIG. 4B. Animals        administered Placebo (Group 1) and animals administered neat        oltipraz tracked closely together. The maximum mean mucositis        score observed in the vehicle group was 3.13±0.09 and occurred        on Day 16. Animals dosed with neat oltipraz (Group 2)        experienced peak mean mucositis score on Day 16 at 3.25±0.11. In        contrast, animals administered the formulated oltipraz        composition (Group 3) displayed a substantially and observably        reduced mucositis compared to animals administered Placebo        (Group 1) or neat oltipraz (Group 2). Supporting this        observation, animals receiving the formulated oltipraz        composition (Group 3) displayed a peak mean mucositis score of        only 2.63±0.13 on Day 16.    -   Over the course of the study, the percentage of animal days with        an ulcerative mucositis (score of≥3) in the placebo Group was        58.33%. In contrast, the percentage of animal-days with a score        of≥3 was dramatically lower for animals in administered the        formulated oltipraz composition (43.75%; p=0.006).

Weight Change

The mean daily percent body weight change data are shown in FIG. 4A foranimals in all groups. All animals gained weight steadily over thecourse of the study (Days −3 to 28), however, animals administered neatoltipraz (Group 2) gained weight at a slower rate than thoseadministered placebo (Group 1) or those administered formulated oltiprazcomposition (Group 3), suggesting that administration of neat oltiprazmay negatively impact weight gain. There were no significant differencesin cumulative mean percent weight change between groups in comparing thearea under the body weight versus time curve (AUC) analysis followed byevaluation with one-way ANOVA and Holm- Sidak's multiple comparisonstest (inset), although as shown in in FIG. 4A, the overall percentageweight change for the animals administered neat oltipraz (Group 2) wassubstantially less than rate than those administered placebo (Group 1)and lower still as compared against those administered formulatedoltipraz composition (Group 3). The percentage rate of weight change foranimals administered neat oltipraz was substanially less than the ratefor those administered placebo or formulated oltipraz.

Mucositis Scoring

Mucositis was scored visually by comparison to a validated photographicscale, ranging from 0 for normal, to 5 for severe ulceration (clinicalscoring). In descriptive terms, this scale is defined as described inTable 7 below:

TABLE 7 Score Description 0 Pouch completely healthy. No erythema orvasodilation. 1 Light to severe erythema and vasodilation. No erosion ofmucosa. 2 Severe erythema and vasodilation. Erosion of superficialaspects of mucosa leaving denuded areas. Decreased stippling of mucosa.3 Formation of off-white ulcers in one or more places. Ulcers may have ayellow/gray color due to pseudomembrane. Cumulative size of ulcersshould equal less than or equal to ¼ of the pouch. Severe erythema,andvasodilation. 4 Cumulative seize of ulcers should equal about ½ of thepouch. Loss of pliability. Severe erythema and vasodilation. 5 Virtuallyall of pouch is ulcerated. Loss of pliability (pouch can only partiallybe extracted from mouth).

Duration of Ulcerative Mucositis

A mucositis score of 3 or greater indicates ulcerative mucositis, aclinically significant threshold. To quantify the clinical significanceof differences observed between the control and treatment groupsanimal-days with mucositis scores≥3 and <3 were compared between groupsusing chi-square analysis. The results of this analysis are shown inTable 8 and FIG. 5 for the entire study duration (through Day 28). Overthe course of the study (Table 8, FIG. 5), the percentage of animal dayswith a score of≥3 in the vehicle Group was 58.33%. The percentage ofdays with a score of≥3 was dramatically and statistically lower foranimals in Group 3 in comparison to the vehicle Group (Group 1; p<0.01).

Table 8 below provides a chi-square analysis of percent of animal dayswith a mucositis score≥3. To examine the levels of clinicallysignificant mucositis, as defined by presentation with open ulcers(score≥3), the total number of days in which an animal exhibited anelevated score was summed and expressed as a percentage of the totalnumber of days scored for each group. Statistical significance ofobserved differences was calculated using chi-squared analysis.

TABLE 8 Chi-Square Analysis of Percent of Animal Days with a MucositisScore ≥ 3 Total Chi Days Days Animal % Days Sq vs. P Treatment ≥3 <3Days ≥3 Vehicle Value Group 1: Placebo 112 80 192 58.33% — — Group 2:Neat oltipraz 104 88 192 54.17% 0.519 0.471 Group 3: Formulated 84 108192 43.75% 7.597 0.006 oltipraz composition

FIG. 5 provides a graph of the percent of animal days with mucositisscores≥3 for the entire study duration. To examine the levels ofclinically significant mucositis, as defined by presentation with openulcers (a score of≥3), the total number of days in which an animalexhibited an elevated score was summed and expressed as a percentage ofthe total number of days scored for the entire study duration (Day6-28). Statistical significance was evaluated using the Chi-square testin comparison to Vehicle Control; The statistical significance for theGroup 3 results (**) was p<0.01.

Mucositis Severity

An analysis of the severity of mucositis was performed using theMann-Whitney rank sum analysis to compare the visual mucositis scoresfor Groups 2 and 3 to the vehicle control group (Group 1) on each day ofthe analysis. The results of this analysis are shown in Table 9 below.In this analysis, 2 consecutive days of significant reduction in themucositis score are generally required before it is regarded asclinically meaningful. Animals dosed with the formulated oltiprazcomposition (Group 3) demonstrated four instances of significantimprovement in mucositis scores compared to the vehicle control groupincluding a stretch of four consecutive days of statisticallysignificant improvement (Days 14-18) compared to animals administeredPlacebo (Group 1).

TABLE 9 Comparison of Daily Mucositis Scores. Rank Sum Analysis by DayGroup 6 8 10 12 14 16 18 20 22 24 26 28 Placebo 0.4839 0.1539   0.91810.2734 0.4839    0.6539    1.0     0.4839 1.0 0.2734    0.2734 0.7043vs. Neat Oltipraz Placebo 0.1012 <0.0001 x, y 0.6774 0.7430 0.0177 x, z0.0321 x, z 0.0321 x, z 0.1012 0.1012 0.0242 x, z 0.7224 0.4320 vs. For-mulated Oltipraz Compo- sition

The significance of group differences observed in daily mucositis scoreswas determined using the Mann-Whitney rank sum test. This nonparametricstatistic is appropriate for the visual mucositis scoring scale. Thep-values for each calculation are shown. “x” denotes significantdifference in mucositis scores. “y” denotes increase in comparison tovehicle Group (improvement), “z” denotes decrease.

Percent of Animals with Ulcerative Mucositis by Day

The percentage of animals in each group with ulcerative mucositis ateach day of evaluation is shown in Table 10. This evaluation wasintended to clarify which days of treatment had its maximal impact onthe course of ulcerative mucositis. Fewer animals displayed ulcerativemucositis when administered the formulated oltipraz composition (Group3) over ten consecutive day (Days 14-24) in comparison to the animalsreceiving Placebo (Group 1).

TABLE 10 Percent of Animals with Ulceration by Day with Mucositis Score≥ 3. Percent Ulceration by Day (Score ≥ 3) Group 6 8 10 12 14 16 18 2022 24 26 28 Group 1: Placebo 0.0 0.0 12.5   25.0 100.0 100.0 100.0 100.0100.0 75.0  50.0  37.5 Group 2: Neat Oltipraz 0.0 0.0 0.0 z  50.0 y100.0 100.0 100.0 100.0 100.0 50.0 z 25.0 z  25.0 z Group 3: Formulated0.0 0.0 0.0 z 25.0   62.5 z   75.0 Z   75.0 z   75.0 z   75.0 z 37.5 z62.5 y 37.5 Oltipraz Composition

To examine the levels of clinically significant mucositis, as defined bypresentation with open ulcers (score≥3), the percentage of animals fromeach treatment group that exhibited an open ulcer on each day of thestudy was determined. “y” denotes an increase in comparison to vehicleGroup, “z” denotes decrease (improvement). The results show animprovement in the ulceration scores for the formulated oltiprazcomposition as compared to either the neat oltipraz or placebo. Theresults of day 26 appears to have been due to one animal flare from day24 and the result of day 28 is likely due to the difference in a singleanimal score.

Conclusions

-   -   There were no animal deaths at any time during this study.    -   There were no significant differences in overall mean percent        weight change between the placebo control group and the        treatment groups from Day −3 to 28, although as shown in in FIG.        4A, the overall percentage weight change for the animals        administered neat oltipraz (Group 2) was substantially less than        rate than those administered placebo (Group 1) and lower still        as compared against those administered formulated oltipraz        composition (Group 3).    -   The maximum mean mucositis score observed in the placebo group        was 3.13 ±0.09 and occurred on Day 16. Animals dosed with neat        oltipraz (Group 2) experienced peak mean mucositis score on Day        16 at 3.25±0.11. Animals dosed with the formulated oltipraz        composition (Group 3) experienced peak mean mucositis score of        2.63±0.13 and first occurred on Day 14.    -   Over the course of the study, the percentage of animal days with        an ulcerative mucositis (score of≥3) in the placebo Group was        58.33%. In contrast, the percentage of animal-days with a score        of >3 was dramatically lower for animals administered the        formulated oltipraz composition (43.75%; p=0.006)

Example 4: Qualitative Visual Assessment of Oltipraz Compositions

As noted above, the stability of the oltipraz crystals in an aqueoussuspension can be assessed in 3 ways. First, they can be assessed by DLSto determine whether there is an increase in the MHD. Second, thepotency (and thus the stability) of the suspension can be can bedetermined by sampling the top of the suspension, making sure not to mixany precipitate back into the suspension. The concentration of drug inthe suspension should not decrease by a predetermined amount in a givenperiod, e.g., by more than a predetermined amount e.g., 1%, 2%, 5%, 10%,15% or 20% in a period selected from 1 minute, 5 minutes, 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 6 hours, 12 hours and 24 hours.

The third way is by a qualitative visual assessment. With asubstantially stable suspension, after 24 hours of the suspensionsitting un-agitated at ambient temperature (e.g., 25° C.), only aminimal amount of solids will form at the bottom of the container andthe remaining suspension should not qualitatively change in either coloror appearance. Suspensions that are not stable for predetermined periodswill exhibit significant settling, a shift to more reddish color of thesuspension, or a change in the opacity of the suspension. FIG. 6illustrates a comparison of various suspensions prepared from spraydried compositions comprising oltipraz crystals prepared generallyaccording to the method described in Example 1. The spray driedcompositions were diluted in preparation for analysis by DLS and thenallowed to stand without agitation. As can be seen, Sample D, which wasprepared using Dextran 40 as the bulking agent, evidenced significantsettling and an increase in the transparency of the suspension,indicating that this particular composition was not stable for aprolonged period. The compositions of the five samples is shown in Table11 below:

TABLE 11 Component Sample A Sample B Sample C Sample D Sample E ST-617API 14.8% 14.8% 14.8% 14.8% 14.8% Eudragit RL  7.5%  7.5%  7.5%  7.5% 7.5% Tween 80  3.6%  3.6%  3.6%  3.6%  3.6% PVP VA64 74.0% Kollidon 3074.0% Geismar Trehalose 74.0% Dextran 40 74.0% HPMC-E3 74.0%

Example 5: Solubility Analysis of Oltipraz Compositions

The solubility of oltipraz crystals in a spray-dried compositionprepared generally according to the method described in Example 1 wasmeasured and compared against the solubility of neat crystallineoltipraz prepared according to the process disclosed in WO2016207914.The MHD of the oltipraz crystals in the spray-dried composition was369.5 nm, with a polydispersity of 0.324 as measured by DLS afterreconstituting the powder in water. The crystals in the neat crystallineoltipraz ranged in size from 20 μm to 200 μm. The solubility wasdetermined at 20° C. both in water and in standard 2% simulatedintestinal fluid (Fisher Scientific, USA. Catalog No. 7109-16). Theresults are reported in Table 12 below.

TABLE 12 Measured Solubility μg/mL Sample Condition (mean n= 2) Neatoltipraz in water  3.1 Solubility of active ingredient (oltiprazcrystals)  5.7 in spray-dried composition in water Neat oltipraz in 2%simulated intestinal fluid 15.8 Solubility of active ingredient(oltipraz crystals) 22.6 in spray-dried composition in in 2% simulatedintestinal fluid

As can be seen, the solubility of the oltipraz crystals in water almostdoubled as compared to the neat oltipraz crystals, showing an increaseof 83%. The increase in the simulated intestinal fluid was greater than40%, i.e., approximately 43%.

Example 6: Lyophilization of Oltipraz Compositions

An 87.5 mg sample containing 50 mg of oltipraz crystals that werenano-milled to less than 300 nm particle size, 25 mg of Eudrogit and12.5 mg of Tween80 was added to a 5 ml aqueous solution containing 495mg of PVP-VA64. The sample was frozen with dry ice and subjected tostandard lyophilization (freeze drying) on a Labconco lyophilizer at10×10(−4) mbar vacuum for 4 hours. The resultant powder was compared topowder that was formed by spray drying the same suspension and was foundto have substantially the same bulk density and physical characteristicsas the sample prepared in Example 1.

Example 7: MTT Cell Viability and Intracellular ROS Assays using HGEPpCells

Accumulation of reactive oxygen species (ROS) coupled with an increasein oxidative stress is implicated in the pathogenesis of many diseases.Free radicals and other reactive species are constantly generated invivo and cause oxidative damage to biomolecules, a process held in checkby multiple antioxidant and repair systems. Recrystallized oltipraz(prepared according to the process disclosed in WO2016207914) and aformulated oltipraz composition prepared generally according to theprocess described in Example 1 were tested to determine their effect onprotecting primary human gingival epithelial cells (HGEPp) cells fromoxidative damage induced by hydrogen peroxide (H2O2). Both treatmentsshowed a statistically significant decrease in intracellular ReactiveOxygen Species concentrations in HGEPp cells at 95% confidence level.The formulated oltipraz composition showed a higher protective effectcompared to the recrystallized oltipraz at an 80% confidence level. Thedata showed a numerical increase in the level of protective activity forthe formulated oltipraz compositions as compared to the recrystallizedoltipraz. The data did reveal a statistically significant decrease inintracellular ROS (P<0.2) for the formulated oltipraz composition ascompared to the recrystallized oltipraz.

Objectives

1. measure the effect of recrystallized oltipraz, formulated oltiprazcomposition and control powder on cell proliferation within HGEPp cellstreated with H2O2, using the TACS MTT Cell Viability Assay Kit

2. measure the effect of recrystallized oltipraz amd formulated oltiprazon hydroxyl, peroxyl and other reactive oxygen species within HGEPpcells, using Cell Biolabs' OxiSelect™ Intracellular ROS Assay Kit. Thisassay employs the cell-permeable fluorogenic probe2′,7′-dichlorodihydrofluorescin diacetate (DCFH-DA) which diffuses intocells and is deacetylated by cellular esterases to a nonfluorescent DCFHwhich is then rapidly oxidized to highly fluorescent2′,7′-dichlorodihydrofluorescein (DCF) by ROS.

Materials

-   -   Recrystallized oltipraz prepared by Supportive Therapeutics LLC        (Appearance: Red Powder (98.6% HPLC purity)    -   Formulated oltipraz crystals (Supportive Therapeutics LLC),        prepared as described above in Example 1. The MHD of the        crystals, as measured by dynamic light scattering (DLS), was        about 300 nm. (Appearance: Red Powder)    -   Control Powder (Supportive Therapeutics LLC) prepared as        described above in Example 1, but with no oltipraz crystals        (Appearance: Red Powder)    -   HGEPp cells were purchased from CellnTec Advanced Cell Systems        AG    -   TACS MTT Cell Viability Kit was purchased from Trevigen Inc.,        USA    -   OxiSelect™ Intracellular ROS Assay Kit was purchased from Cell        Biolabs Inc USA.

METHODS Cell Culture

Pooled primary HGEPps were propagated in CnT-Prime epithelial culturemedium provided by CellnTec on 100 mm petri dishes coated with 30 mg/mlType I rat tail collagen (BD Biosciences) diluted in Dulbecco'sphosphate-buffered saline (DPBS). This cell type was chosen since theformulated oltipraz compositions described herein have the potential toserve as a treatment for oral mucositis in a suspension formulation,thereby putting such compositions in close contact with HGEPp cells. Thecells were harvested when they reached 70-90% confluency as observed bylight microscopy. For routine cultivation, the medium was changed every3 days. For both the cell viability and ROS assays, the cells frompassages 3-7 were seeded at 5×10 3 , 2.5×10 4 , 5×10 4 cells/cm 2density to grow cell monolayers in 24-well flat-bottomed tissue cultureplates and acclimated overnight at 37° C.

Preparation of Dosing Solutions

-   -   1. Recrystallized oltipraz was received as a powder from        Supportive Therapeutics and a 100 mM DMSO stock was prepared.        Further dilutions were prepared in DMSO from the 100 mM DMSO        stock and each DMSO dilution was then added into 10 mL of        Dulbecco's phosphate-buffered saline to arrive at final        concentrations of 10, 50, and 100 μM.    -   2. The Normal (Control) group contained saline with the same        percentage of DMSO as the treated group.    -   3. All dosing solutions contained 0.3% of DMSO which is well        below the maximum tolerated DMSO percent of 0.8% for HGEPp        cells.    -   4. Formulated oltipraz crystals and control powder were received        as a powder and a 500 mM DMSO stock solution was prepared for        each powder.    -   5. 5× dilutions were prepared in DMSO from the 500 mM DMSO stock        and each DMSO dilution was then added into 10 mL of Dulbecco's        phosphate-buffered saline to arrive at final concentrations of        10, 50, and 100 μM of formulated oltipraz composition and        control powder.

Cell Survival Assay (TACS MTT Kit)

-   -   1. Plate cell concentration was selected to be 6.25×10 5/ml to        yield an OD absorbance within the linear portion of the control        curve.    -   2. Once the HGEPp cells were cultured and ready on the        microplate, the media was removed from all the wells and        discarded. The cells were washed gently with DPBS 2-3 times and        the last wash removed and discarded.    -   3. Added 10 ul of MTT reagent to each well.    -   4. Incubated the plate for 6 hours at 37° C. Viewed the cells to        confirm the appearance of intracellular precipitate using an        inverted microscope.    -   5. Added 100 ul of Detergent Reagent to all wells, including the        control wells taking care not to shake the plates    -   6. Left the plate covered in the dark at room temperature        overnight.    -   7. Removed the plate cover and measured the absorbance of the        wells, including the blanks at 570 nm.    -   8. Determined the average values from triplicate readings after        subtracting the average value for the blanks.

Oxidative Stress Measurement ROS Assay (OxiSelect Kit)

-   -   1. Prepared and mixed all reagents thoroughly before use. (Kit        instruction)    -   2. Once the HGEPp cells were cultured and ready on a microplate,        the media was removed from all the wells and discarded. Washed        the cells gently with DPBS 2-3 times. Removed the last wash and        discarded it.    -   3. Added 100 μL of 1X DCFH-DA/media solution to the cells.        Incubated at 37° C. for 60 minutes. Removed and discarded the        solution.    -   4. Treated the DCFH-DA loaded cells with recrystallized        oltipraz, formulated oltipraz composition and control powder at        the targeted concentrations and with saline/DMSO control.    -   5. Fluorescence was read on a Fluorescence Plate Reader after 1        hour. All treatment media was carefully removed from the wells        and discard. The cells were washed 3 times gently with DPBS.        Added 100 μL of medium to each well. Added 100 μL of the 2× Cell        Lysis Buffer, mixed thoroughly and incubated for 5 minutes.        Transferred 150 μL of the mixture to a fresh 24-well plate for        fluorescence measurements at 530 nm.

RESULTS H2O2-Induced Cytotoxicity in a Dose-Dependent Manner

HGEPp cells were exposed to different concentrations of H2O2 for 4 h toexamine H2O2-induced oxidative stress. The cells were exposed to 0-0.6mM H2O2 for 4 h and cell viability was evaluated using the TACS MTT CellProliferation Assay Kit. The percentage of cell survival was determinedusing the ratio of the optical density (OD) of the test sample to the ODof the control×100%. The results showed that H2O2 exposure led tooxidative stress in a concentration-dependent manner. There was 48%reduction in cell number when the cells were treated with 0.3 mM H2O2(FIG. 7). Therefore, this concentration was taken to be IC50 of H2O2 inHGEPp cells and used in the follow-on experiments. The data is mean+/−SD of 3 experiments in 6 replicate wells.

Effect on H2O2-Induced Oxidative Stress in HGEPp

Incubation of HGEPp with H2O2 decreased cell viability significantly(FIG. 7). This viability was modulated by the recrystallized oltiprazand the formulated oltipraz composition, but not by the control powder(FIG. 8). The results indicate that recrystallized oltipraz andformulated oltipraz composition at the concentrations in the range from50 to 800 □g/ml promoted cell proliferation and reduced H2O2-induceddecrease in HGEPp survival.

Normal control cells were cultured in DPBS containing 0.3% DMSO.Positive Control (PC): oxidative stressed group cells after treatmentwith 0.3 mM H2O2 for 4 h. The remaining groups of cells were pretreatedfor 24 h with recrystallized oltipraz, formulated oltipraz composition,and the control powder at 12.5, 25, 50, 100, 200, 400, 800 μg/mL) priorto treatment with H2O2. The percentage of cell survival was determinedby the ratio of the optical density (OD) of the test samples to the ODof the control×100%. The data are presented as the means +/− SD ofmeasurements that were performed in triplicate in six replicate wells,*P<0.05 for recrystallized oltipraz and formulated oltipraz compositionsbetween 50-800 ug/ml versus the PC. The data shows a numerical increasein the level of protective activity for the formulated oltiprazcomposition as compared to the recrystallized oltipraz.

Effect on ROS Production in HGEPp Cells

The formation of reactive oxygen species (ROS) is indicative ofoxidative stress. There were significantly higher ROS levels (128%) inH2O2-treated hGEP cells compared to normal control cells (100%). Theresults indicate that recrystallized oltipraz and the formulatedoltipraz composition at 100 ug/ml and 200 ug/ml significantly reducedROS levels in H2O2 treated HGEPp cells. (FIG. 9)

Normal: Normal control cells were cultured in DPBS containing 0.3% DMSO.Positive Control (PC): oxidative stressed group cells after treatmentwith 0.3 mM H2O2 for 4 h. The remaining groups of cells were pretreatedfor 24 h with recrystallized oltipraz and formulated oltiprazcomposition, respectively, at 50, 100, 200 μg/mL prior to treatment withH2O2 .

Intracellular ROS was measured using a Spectramax M3 microplate reader.The data are presented as the means +/− SD of measurements that wereperformed in triplicate in six replicate wells, *P<0.05 forrecrystallized oltipraz and formulated oltipraz composition at 100 and200 ug/ml versus the PC. The data also shows a statistically significant(80%) decrease in intracellular ROS (P<0.2) for the formulated oltiprazcomposition as compared to the recrystallized oltipraz. That is, thedata shows a statistically significant (80% confidence level)superiority for the formulated oltipraz composition as compared to therecrystallized oltipraz.

The pharmaceutical compositions and methods of administering thepharmaceutical compositions of this disclosure thus may be used to treatany human or non-human animal patient to decrease intracellular reactiveoxygen species (ROS) and/or decrease oxidative stress, including inpatients undergoing treatments that provide oxidative stress such aschemotherapy or radiation therapy. The pharmaceutical compositions andmethods of administering the pharmaceutical compositions of thisdisclosure may be used to treat any human or non-human animal patient toprovide an antioxidant effect, including in patients undergoingtreatments that provide oxidative stress such as chemotherapy orradiation therapy. The pharmaceutical compositions and methods ofadministering the pharmaceutical compositions of this disclosure alsomay be used to slow the onset, and/or reduce the severity, and/or reducethe duration of oxidative damage in patients (e.g., mucositis, includingoral mucositis), including in patients undergoing treatments thatprovide oxidative damage such as chemotherapy or radiation therapy.

Example 8: Relative Expression of Stress Genes

The Nrf2 system is considered to be a major cellular defense mechanismagainst oxidative damage by activating genes that encode phase IIdetoxifying and antioxidant enzymes. The Human oxidative stress PCRarray was used to evaluate the relative expression of 84 stress genesafter pretreating with 100 uM of recrystallized oltipraz (preparedaccording to the process disclosed in WO2016207914), formulated oltiprazcomposition prepared generally in accordance with the process describedin Example 1 (MHD less than about 350 nm) and negative control(formulated oltipraz composition without the oltipraz) within HGEPpcells. Total RNA was isolated from treated HGEPp cells, purified andreverse transcription was used to generate cDNA. This was combined withthe Qiagen RT2 SYBR Green ROX 96-well array kit and after thermalcycling (BioRad), the gene expressions were recorded (MyiQ detectionsystem) and converted to Fold Change using the Qiagen on-line dataanalysis tool.

The negative control showed no change in any gene regulation. Therecrystallized oltipraz and formulated oltipraz composition both showedup-regulation at Fold Change>2 for ALOX12, GPX1, GCLC, GCLM, NQO1, SOD1and GAPDH genes and down-regulation at Fold Change>2 for GTF2I, PTGS1and UCP2 genes.

Only the formulated oltipraz composition additionally showedup-regulation of GPX4 (glutathione peroxidase 4 -which is specific tocell membrane antioxidant activity) and MPO (myeloperoxidase) anddown-regulation of PRDX2 (Peroxiredoxin 2) at a Fold Change>2.

The pharmaceutical compositions and methods of administering thepharmaceutical compositions of this disclosure thus may be used to treatany human or non-human animal patient to increase the gene expression ofGPX4 and/or MPO. The pharmaceutical compositions and methods ofadministering the pharmaceutical compositions of this disclosure thusalso may be used to treat any human or non-human animal patient todecrease the gene expression of PRDX2. The pharmaceutical compositionsand methods of administering the pharmaceutical compositions of thisdisclosure thus also may be used to treat any human or non-human animalpatient to increase the gene expression of GPX4 and/or MPO and decreasethe gene expression of PRDX2.

Recitation of Embodiments

1. A composition comprising a quantity of crystals, wherein the quantitysubstantially comprises crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione having an intensityaveraged, mean hydrodynamic diameter (Z-average) (“MHD”) of from 30 to2000 nm,

-   -   wherein the MHD is determined performing dynamic light        scattering at 25° C. on a suspension of the crystals in water at        a concentration of 0.01 to 0.1 mg of crystals per mL of water.

2. A composition according to embodiment 1, wherein the quantitysubstantially comprises crystals that have a MHD in the range of from 30to 100 nm.

3. A composition according to embodiment 1, wherein the quantitysubstantially comprises crystals that have a MHD in the range of from100 to 1200 nm.

4. A composition according to embodiment 1, wherein the quantitysubstantially comprises crystals that have a MHD in the range of from150 to 600 nm.

5. A composition according to embodiment 1, wherein the quantitysubstantially comprises crystals that have a MHD in the range of from150 to 450 nm.

6. A composition according to embodiment 2, wherein the compositioncomprises at least one stabilizing agent, and wherein the quantitysubstantially comprises crystals that will have a MHD in the range offrom 30 to 100 nm if left in water at 25° C. for 1 hour.

7. A composition according to embodiment 2, wherein the compositioncomprises at least one stabilizing agent, and wherein the quantitysubstantially comprises crystals that will have a MHD in the range offrom 30 to 100 nm if left in water at 25° C. for 1 hour.

8. A composition according to embodiment 3, wherein the compositioncomprises at least one stabilizing agent, and wherein the quantitysubstantially comprises crystals that will have a MHD in the range offrom 100 to 1200 nm if left in water at 25° C. for 1 hour.

9. A composition according to embodiment 3, wherein the compositioncomprises at least one stabilizing agent, and wherein the quantitysubstantially comprises crystals that will have a MHD in the range offrom 100 to 1200 nm if left in water at 25° C. for 24 hours.

10. A composition according to embodiment 4, wherein the compositioncomprises at least one stabilizing agent, and wherein the quantitysubstantially comprises crystals that will have a MHD in the range offrom 150 to 600 nm if left in water at 25° C. for 1 hour.

11. A composition according to embodiment 4, wherein the compositioncomprises at least one stabilizing agent, and wherein the quantitysubstantially comprises crystals that will have a MHD in the range offrom 150 to 600 nm if left in water at 25° C. for 24 hours.

12. A composition according to embodiment 5, wherein the compositioncomprises at least one stabilizing agent, and wherein the quantitysubstantially comprises crystals that will have a MHD in the range offrom 150 to 450 nm if left in water at 25° C. for 1 hour.

13. A composition according to any of embodiments 1-12, wherein thecomposition comprises less than 1 percent of drug-degradant impuritiesrelative to 4-methyl-5-(pyrazin-2-yl)-3H-1, 2-dithiole-3-thione in theaqueous composition and less than 2 percent total impurities relative tothe 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the aqueoussuspension.

14. A composition according to any of embodiments 1-12, wherein thecomposition comprises less than 0.1 percent of drug-degradent impuritiesrelative to 4-methyl-5-(pyrazin-2-yl)-3H-1, 2-dithiole-3-thione in theaqueous composition and less than 0.5 percent total impurities relativeto the 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the aqueoussuspension.

15. A composition according to any of embodiments 1-14, wherein thepolydispersity index (PdI) of the crystals in the quantity is less than0.80, wherein PdI=(σ/d)², wherein σ is the standard deviation and d isthe mean hydrodynamic diameter (Z-average).

16. A composition comprising a quantity of crystals according toembodiment 15, wherein the polydispersity index (PdI) of the crystals inthe quantity is less than 0.60.

17. A composition comprising a quantity of crystals according toembodiment 15, wherein the polydispersity index (PdI) of the crystals inthe quantity is between 0.10 and 0.60.

18. A composition comprising a quantity of crystals according toembodiment 15, wherein the polydispersity index (PdI) of the crystals inthe quantity is between 0.10 and 0.45.

19. An composition according to any of embodiments 1-18, wherein thequantity of crystals comprises substantially the entire quantity of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione present in thecomposition.

20. A composition according to any of embodiments 5-19, wherein the atleast one stabilizing agent comprises a polymer.

21. A composition according to embodiment 20, wherein the polymer is acationic or anionic polymer.

22. A composition according to embodiment 21, wherein the polymer is acationic polymer.

23. A composition according to embodiment 22, wherein the cationicpolymer comprises ammonium functionality.

24. A composition according to embodiment 22, wherein the cationicpolymer comprises quaternary ammonium functionality.

25. A composition according to any of embodiments 21-24, wherein thecationic polymer is a polymer that is formed from polymerization ofcompounds comprising at least one acrylate-containing compound.

26. A composition according to any of embodiments 21-25, wherein thecationic polymer comprises Poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2(Eudragit RL).

27. A composition according to any of embodiments 1-19, wherein the atleast one stabilizing agent comprises a surfactant.

28. A composition according to any of embodiments 20-26, wherein thecomposition comprises a surfactant.

29. A composition according to embodiment 27 or 28, wherein thesurfactant is a nonionic surfactant.

30. A composition according to embodiment 27-29, wherein the surfactantis a sorbitan ester.

31. A composition according to any of embodiments 27-30, wherein thesurfactant is polyethylene glycol sorbitan monooleate.

32. A composition according to embodiment 27 or 28, wherein thesurfactant is selected from the group consisting of polyethylene glycolsorbitan monooleate surfactants, polyethylene glycol hydrogenated castoroil, block copolymers of poly(ethylene oxide) and poly(propylene oxide),sodium lauryl sulfate, benzalkonium chloride, and sodium docusate.

33. A composition according to any of embodiments 1-19, wherein thecomposition comprises a bulking agent.

34. A composition according to any of embodiments 20-26, wherein thecomposition comprises a bulking agent.

35. A composition according to embodiment 27, wherein the compositioncomprises a bulking agent.

36. A composition according to any of embodiments 28-32, wherein thecomposition comprises a bulking agent.

37. A composition according to any of embodiments 5-19, wherein the atleast one stabilizing agent comprises a bulking agent.

38. A composition according to any of embodiments 33-37, wherein thebulking agent comprises a polyvinylpyrrolidone compound.

39. A composition according to embodiment 38, wherein the bulking agentcomprises a copolymer of polyvinylpyrrolidone and poly(vinyl acetate)with a ratio of approximately 6:4 of vinylpyrrolidone and vinyl acetatemonomers (PVP-VA64).

40. A composition according to any of embodiments 1-19, wherein thecomposition comprises water.

41. A composition according to any of embodiments 1-19, wherein thecomposition comprises a non-aqueous solvent.

42. A composition according to embodiment 40 or 41, wherein the quantityof crystals comprise from 4 to 15 percent by weight of the composition.

43. A composition according to embodiment 40 or 41, wherein the quantityof crystals comprise from 6 to 12 percent by weight of the composition.

44. A composition according to embodiments 20-26, wherein thecomposition comprises water.

45. A composition according to any of embodiments 20-26, wherein thecomposition comprises a non-aqueous solvent.

46. A composition according to embodiment 44 or 45, wherein the quantityof crystals comprise from 4 to 15 percent by weight of the compositionand the polymer comprises from 7.5 percent to 25 percent by weight ofthe composition.

47. A composition according to any of embodiments 27-32, wherein thecomposition comprises water.

48. A composition according to any of embodiments 27-32, wherein thecomposition comprises a non-aqueous solvent.

49. A composition according to embodiment 47 or 48, wherein the quantityof crystals comprise from 4 to 15 percent by weight of the compositionand the surfactant comprises less than 5 percent by weight of thecomposition.

50. A composition according to any of embodiments 28-32, wherein thecomposition further comprises water.

51. A composition according to any of embodiments 28-32, wherein thecomposition comprises a non-aqueous solvent.

52. A composition according to embodiment 50 or 51, wherein the quantityof crystals comprise from 4 to 15 percent by weight of the composition,the polymer comprises from 2 to 10 percent by weight of the composition,and the surfactant comprises less than 5 percent by weight of thecomposition.

53. A composition according to any of embodiments 33-39, wherein thecomposition comprises water.

54. A composition according to any of embodiments 33-39, wherein thecomposition comprises a non-aqueous solvent.

55. A composition according to embodiment 53 or 54, wherein the quantityof crystals comprise from 1 to 10 percent by weight of the compositionand the bulking agent comprises from 10 to 30 percent by weight of thecomposition.

56. A composition according to any of embodiments 34-39, wherein thecomposition comprises water.

57. A composition according to any of embodiments 34-39, wherein thecomposition comprises a non-aqueous solvent.

58. A composition according to embodiment 56 or 57, wherein the quantityof crystals comprise from 1 to 10 percent by weight of the composition,the polymer comprises less than 5 percent by weight of the composition,and the bulking agent comprises from 10 to 30 percent by weight of thecomposition.

59. A composition according to any of embodiments 35-39, wherein thecomposition comprises water.

60. A composition according to any of embodiments 35-39, wherein thecomposition comprises a non-aqueous solvent.

61. A composition according to embodiment 60 or 61, wherein the quantityof crystals comprise from 1 to 10 percent by weight of the composition,the surfactant comprises less than 4 percent by weight of thecomposition, and the bulking agent comprises from 10 to 30 percent byweight of the composition.

62. A composition according to any of embodiments 36-39, wherein thecomposition comprises water.

63. A composition according to any of embodiments 36-39, wherein thecomposition comprises a non-aqueous solvent.

64. A composition according to embodiment 61, wherein the quantity ofcrystals comprise from 1 to 10 percent by weight of the composition, thepolymer comprises less than 5 percent by weight of the composition, thesurfactant comprises less than 4 percent by weight of the composition,and the bulking agent comprises from 10 to 30 percent by weight of thecomposition.

65. A composition according to any of embodiments 33-39, wherein thecomposition substantially excludes water and any non-aqueous solvent.

66. A composition according to embodiment 65, wherein the bulking agentcomprises from 50 to 90 percent by weight of the composition.

67. A composition according to embodiment 65, wherein the bulking agentcomprises from 60 to 85 percent by weight of the composition.

68. A composition according to any of embodiments 34-39, wherein thecomposition substantially excludes water and any non-aqueous solvent.

69. A composition according to embodiment 68, wherein the bulking agentcomprises from 50 to 90 percent by weight of the composition, and thepolymer comprises from 3 to 12 percent by weight of the composition.

70. A composition according to any of embodiments 35-39, wherein thecomposition substantially excludes water and any non-aqueous solvent.

71. A composition according to embodiment 70, wherein the bulking agentcomprises from 50 to 90 percent by weight of the composition, and thesurfactant comprises from 1 to 8 percent by weight of the composition.

72. A composition according to embodiment 70, wherein the bulking agentcomprises from 60 to 85 percent by weight of the composition, and thesurfactant comprises from 1 to 6 percent by weight of the composition.

73. A composition according to any of embodiments 36-39, wherein thecomposition substantially excludes water and any non-aqueous solvent.

74. A composition according to embodiment 73, wherein the bulking agentcomprises from 50 to 90 percent by weight of the composition, thepolymer comprises from 3 to 12 percent by weight of the composition, andthe surfactant comprises from 1 to 8 percent by weight of thecomposition.

75. A composition according to embodiment 73, wherein the bulking agentcomprises from 60 to 85 percent by weight of the composition, thepolymer comprises from 5 to 10 percent by weight of the composition, andthe surfactant comprises from 1 to 6 percent by weight of thecomposition.

76. A composition according to any of embodiments 64-75, wherein thequantity of crystals comprises from 5 to 25 percent by weight of thecomposition.

77. A composition according to any of embodiments 64-75, wherein thequantity of crystals comprises from 10 to 20 percent by weight of thecomposition.

78. A composition according to any of embodiments 64-75, wherein thequantity of crystals comprises from 12 to 17 percent by weight of thecomposition.

79. A composition according to any of embodiments 64-75, wherein thecomposition substantially excludes water, and wherein the composition iscapable of forming a substantially complete aqueous suspension of aquantity of crystals.

80. A composition according to embodiment 79, wherein the compositionwill form a substantially complete aqueous suspension with vigorousshaking in less than 15 minutes if mixed with water at a weight : weightratio of 1 part of the dry composition per 10 parts of water at 25° C.

81. A composition according to embodiment 79, wherein the compositionwill form a substantially complete aqueous suspension with vigorousshaking in less than 10 minutes if mixed with water at a weight : weightratio of 1 part of the dry composition per 10 parts of water at 25° C.

82. A composition according to embodiment 79, wherein the compositionwill form a substantially complete aqueous suspension with vigorousshaking in less than 5 minutes if mixed with water at a weight : weightratio of 1 part of the dry composition per 10 parts of water at 25° C.

83. A composition according to embodiment 79, wherein the compositionwill form a substantially complete aqueous suspension with vigorousshaking in less than 2 minutes if mixed with water at a weight : weightratio of 1 part of the dry composition per 10 parts of water at 25° C.

84. A composition according to any of embodiment 79, wherein thecomposition will form a substantially complete aqueous suspension withvigorous shaking in less than 1 minute if mixed with water at a weight :weight ratio of 1 part of the dry composition per 10 parts of water at25° C.

85. A composition according to any of embodiments 64-84 thatsubstantially excludes water, wherein the composition has been made by aprocess comprising spray drying.

86. A composition that substantially excludes water made by a processcomprising spray drying an aqueous formulation comprising water and acomposition according to any of embodiments 1-63.

87. A composition according to any of embodiments 64-84 thatsubstantially excludes water, wherein the composition has been made by aprocess comprising lyophilization.

88. A composition that substantially excludes water made by a processcomprising lyophilizing an aqueous formulation comprising water and acomposition according to any of embodiments 1-63.

89. A dry pharmaceutical composition comprising a composition accordingto any of embodiments 1-39 and 64-88 that substantially excludes waterand any non-aqueous solvent.

90. A dry pharmaceutical composition according to embodiment 89,comprising at least one pharmaceutically acceptable additive.

91. A dry pharmaceutical composition according to embodiment 89 or 90,comprising a pharmaceutically acceptable additive that inhibitsmicrobial growth.

92. A dry pharmaceutical composition according to any of embodiments89-91, comprising a pharmaceutically acceptable lubricant.

93. A dry pharmaceutical composition according to embodiment 92, whereinthe lubricant is magnesium stearate or silica oxide.

94. A dry pharmaceutical composition according to embodiment 92 or 93,wherein the lubricant is present in an amount of up to 2 percent byweight of the pharmaceutical composition.

95. A dry pharmaceutical composition comprising up to 2000 mg of a drypharmaceutical composition according to any of embodiments 89-94.

96. A dry pharmaceutical composition comprising up to 1000 mg of a drypharmaceutical composition according to any of embodiments 89-94.

97. A dry pharmaceutical composition comprising up to 500 mg of a drypharmaceutical composition according to any of embodiments 89-94.

98. A pharmaceutical composition suitable for oral administrationcomprising a liquid and a composition according to any of embodiments1-63.

99. A pharmaceutical composition suitable for oral administrationcomprising a non-aqueous liquid and a composition according to any ofembodiments 1-63.

100. An aqueous pharmaceutical composition suitable for oraladministration comprising water and a composition according to any ofembodiments 1-63.

101. An aqueous pharmaceutical composition prepared by a processcomprising the step of mixing a combination of ingredients comprising aliquid and a dry pharmaceutical composition according to any ofembodiments 89-97.

102. A pharmaceutical composition according to 101, wherein the mixturecomprises, in a weight : weight ratio, 1 part of dry pharmaceuticalcomposition and up to 100 parts of liquid.

103. A pharmaceutical composition according to 101, wherein the mixturecomprises, in a weight : weight ratio, 1 part of dry pharmaceuticalcomposition and up to 60 parts of liquid.

104. A pharmaceutical composition according to 101, wherein the mixturecomprises, in a weight : weight ratio, 1 part of dry pharmaceuticalcomposition and up to 40 parts of liquid.

105. A pharmaceutical composition according to 101, wherein the mixturecomprises, in a weight : weight ratio, 1 part of dry pharmaceuticalcomposition and up to 20 parts of water.

106. A pharmaceutical composition according to any of embodiments101-105, comprising at least one pharmaceutically acceptabletaste-modifying additive.

107. A pharmaceutical composition according to any of embodiments101-106, wherein the liquid comprises water.

108. A pharmaceutical composition according to any of embodiments101-107, wherein the liquid comprises a non-aqueous solvent.

109. A pharmaceutical composition for topical administration to skincomprising a composition according to any of embodiments 1-78 and apharmaceutically acceptable ingredient for topical administration.

110. A pharmaceutical composition for rectal administration comprising acomposition according to any of embodiments 1-78 and a pharmaceuticallyacceptable ingredient for rectal administration.

111. A pharmaceutical composition for colonic administration comprisinga composition according to any of embodiments 1-78 and apharmaceutically acceptable ingredient for colonic administration.

112. A pharmaceutical composition for administration by inhalationcomprising a composition according to any of embodiments 1-39 and 64-99.

113. A medical device comprising an inhaler and a pharmaceuticalcomposition for administration by inhalation according to embodiment112.

114. A process for making a medical device according to embodiment 113comprising loading a dose of a pharmaceutical composition according toembodiment 112 into an inhaler.

115. A pharmaceutical dose for oral administration comprising acomposition according to any of embodiments 1-39 and 64-99.

116. A pharmaceutical composition according to embodiment 115, whereinthe dose is in the form of a pills, tablet or capsule that substantiallyexcludes water.

117. A pharmaceutical composition according to embodiment 115, whereinthe dose is in the form of a liquid.

118. A pharmaceutical composition according to embodiment 117, whereinthe dose is in a soft gel capsule.

119. A pharmaceutically acceptable container for providing an aqueouspharmaceutical composition, comprising a cavity of sufficient size tohold both a dry pharmaceutical composition and a quantity of liquidcomprising an amount of water sufficient to permit mixing of the drypharmaceutical composition to form a liquid composition, wherein the drypharmaceutical composition comprises a composition according to any ofembodiments 1-39 and 64-97 that substantially excludes water and anynon-aqueous solvents.

120. A pharmaceutically acceptable container according to embodiment119, further comprising a releasable coupling for providing an openingin the container adapted to dispense a liquid composition from thecontainer.

121. A pharmaceutically acceptable container according to embodiment119, comprising a compartment separate from the cavity, said compartmentcomprising the dose of the dry pharmaceutical composition.

122. A pharmaceutically acceptable container according to embodiment120, comprising a compartment separate from the cavity, said compartmentcomprising the dose of the dry pharmaceutical composition.

123. A pharmaceutically acceptable container according to embodiment122, wherein the releasable coupling connects the portion of thecontainer comprising the cavity to the portion of the containercomprising the compartment.

124. A pharmaceutically acceptable container according to any ofembodiments 120-123, further comprising a breakable seal between thecompartment and the cavity.

125. A pharmaceutically acceptable container according to any ofembodiments 119-124, further comprising a liquid comprising water.

126. A pharmaceutically acceptable container according to any ofembodiments 119-125, further comprising a liquid comprising anon-aqueous solvent.

127. A pharmaceutically acceptable container according to embodiment 125or 126, wherein the liquid also comprises at least one pharmaceuticallyacceptable taste-modifying additive.

128. A process comprising the step of wet milling a compositioncomprising a liquid and 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione to form a liquid composition comprising crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione,

-   -   wherein wet milling yields a quantity of crystals that have an        intensity averaged, mean hydrodynamic diameter (Z-average)        (“MHD”) of from 100 to 2000, wherein the MHD is determined by        dynamic light scattering at 25° C. and a concentration of 0.01        to 0.1 mg of crystals per mL of water.

129. A process according to embodiment 128, wherein wet milling yields aquantity of crystals that have a MHD of from 100 to 1200 nm.

130. A process according to embodiment 128, wherein wet milling yields aquantity of crystals that have a MHD of from 150 to 600 nm.

131. A process according to embodiment 128, wherein wet milling yields aquantity of crystals that have a MHD of from 150 to 450 nm.

132. A process according to embodiments 128, wherein the compositioncomprises at least one stabilizing agent, and wherein the quantity ofcrystals will have a MHD of from 100 to 2000 nm if left in water at 25°C. for at least 1 hour.

133. A process according to embodiments 132, wherein the quantity ofcrystals will have a MHD in the range of from 100 to 2000 nm if left inwater at 25° C. for 24 hours.

134. A process according to embodiments 129, wherein the compositioncomprises at least one stabilizing agent, and wherein the quantity ofcrystals will have a MHD of from 100 to 1200 nm if left in water at 25°C. for at least 1 hour.

135. A process according to embodiments 134, wherein the quantity ofcrystals will have a MHD of from 100 to 1200 nm if left in water at 25°C. for 24 hours.

136. A process according to embodiments 130, wherein the compositioncomprises at least one stabilizing agent, and wherein the quantity ofcrystals will have a MHD of from 150 to 600 nm if left in water at 25°C. for at least 1 hour.

137. A process according to embodiments 136, wherein the quantity ofcrystals will have a MHD of from 150 to 600 nm if left in water at 25°C. for 24 hours.

138. A process according to embodiments 131, wherein the compositioncomprises at least one stabilizing agent, and wherein the quantity ofcrystals will have a MHD of from 150 to 450 nm if left in water at 25°C. for at least 1 hour.

139. A process according to embodiments 138, wherein the quantity ofcrystals will have a MHD of from 150 to 4500 nm if left in water at 25°C. for 24 hours.

140. A process according to any of embodiments 132-140, wherein thestabilizing agent comprises a polymer.

141. A process according to embodiment 140, wherein the polymercomprises a cationic or anionic polymer.

142. A process according to embodiment 140, wherein the polymer is acationic polymer.

143. A process according to embodiment 142, wherein the cationic polymercomprises ammonium functionality.

144. A process according to embodiment 143, wherein the cationic polymercomprises quaternary ammonium functionality.

145. A process according to any of embodiments 141-144, wherein thecationic polymer comprises a polymer that is formed from polymerizationof compounds comprising at least one acrylate-containing compound.

146. A process according to any of embodiments 141-145, wherein thecationic polymer comprises Poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2(Eudragit RL).

147. A process according to any of embodiments 132-146, wherein thestabilizing agent comprises between 10 and 20 percent by weight of theliquid composition.

148. A process according to any of embodiments 132-146, wherein thestabilizing agent comprises between 12 and 17 percent by weight of theliquid composition.

149. A process according to any of embodiments 128-148, wherein theliquid composition comprises a surfactant.

150. A process according to embodiment 149, wherein the surfactant isselected from the group consisting of polyethylene glycol sorbitanmonooleate surfactants, polyethylene glycol hydrogenated castor oil,block copolymers of poly(ethylene oxide) and poly(propylene oxide),sodium lauryl sulfate, benzalkonium chloride, and sodium docusate.

151. A process according to embodiment 149 or 150, wherein thesurfactant comprises a nonionic surfactant.

152. A process according to any of embodiments 149-151, wherein thesurfactant comprises a sorbitan ester.

153. A process according to any of embodiments 149-152, wherein thesurfactant is polyethylene glycol sorbitan monooleate.

154. A process according to any of embodiments 149-153, wherein thesurfactant comprises from 1 to 5 percent by weight of the composition.

155. A process according to any of embodiments 149-153, wherein thesurfactant comprises from 1 to 3 percent by weight of the composition.

156. A process according to any of embodiments 128-155, wherein thequantity of crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione comprise less than 20percent by weight of the liquid composition.

157. A process according to any of embodiments 128-155, wherein thequantity of crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione comprise less than 15percent by weight of the liquid composition.

158. A process according to any of embodiments 128-155, wherein thequantity of crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione comprise from 5 to 12percent by weight of the liquid composition.

159. A process according to any of embodiments 128-155, wherein thequantity of crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione comprise from 7 to 10percent by weight of the liquid composition.

160. A process according to any of embodiments 128-159, furthercomprising the step of combining a bulking agent with at least a portionof said liquid composition to form a liquid composition comprising thebulking agent and crystals.

161. A process according to embodiment 160, wherein the step ofcombining a bulking agent comprises mixing the bulking agent and aliquid composition comprising the crystals to form an liquid compositioncomprising the bulking agent and crystals.

162. A process according to any of embodiments 160-161, wherein thebulking agent comprises a polyvinylpyrrolidone compound.

163. A process according to any of embodiments 160-162, wherein thebulking agent comprises a copolymer of polyvinylpyrrolidone andpoly(vinyl acetate) with a ratio of approximately 6:4 ofvinylpyrrolidone and vinyl acetate monomers (PVP-VA64).

164. A process according to any of embodiments 128-163, wherein theliquid composition comprises water.

165. A process according to any of embodiments 128-164, wherein theliquid composition comprises a non-aqueous solvent.

166. A process according to any of embodiments 160-165, comprising thestep of adding a liquid comprising water to adjust the percent solidscontent of the liquid composition comprising the bulking agent andcrystals.

167. A process according to any of embodiments 160-166, wherein thebulking agent comprises less than 30 percent by weight of the liquidcomposition comprising the bulking agent and crystals.

168. A process according to any of embodiments 160-166, wherein thebulking agent comprises between 15 and 25 percent by weight of theliquid composition comprising the bulking agent and crystals.

169. A process according to any of embodiments 160-168, wherein theliquid composition comprising the bulking agent and crystals comprisesmore than 35 percent total solids.

170. A process according to any of embodiments 160-168, wherein theliquid composition comprising the bulking agent and crystals comprisesfrom 30 to 35 percent total solids.

171. A process according to any of embodiments 160-168, wherein theliquid composition comprising the bulking agent and crystals comprisesfrom 25 to 30 percent total solids.

172. A process according to any of embodiments 160-168, wherein theliquid composition comprising the bulking agent and crystals comprisesfrom 20 to 25 percent total solids.

173. A process according to any of embodiments 160-168, wherein theliquid composition comprising the bulking agent and crystals comprisesfrom 15 to 20 percent total solids.

174. A process according to any of embodiments 160-168, wherein theliquid composition comprising the bulking agent and crystals comprisesless than 15 percent total solids.

175. A process according to any of embodiments 160-168, wherein theliquid composition comprising the bulking agent and crystals comprisesabout 28 percent total solids.

176. A process according to any of embodiments 160-175 furthercomprising one or more steps to form a dry composition thatsubstantially excludes liquid, wherein the one or more steps comprisethe step of spray drying the liquid composition comprising the bulkingagent and crystals.

177. A process according to any of embodiments 160-175 furthercomprising one or more steps to form a dry composition thatsubstantially excludes liquid, wherein the one or more steps comprisethe step of lyophilizing the liquid composition comprising the bulkingagent and crystals.

178. A process according to any of embodiments 128-175, wherein theliquid composition comprises less than 1 percent of drug-degradentimpurities relative to 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the liquid composition and less than 2 percenttotal impurities relative to the4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the liquidcomposition.

179. A process according to any of embodiments 128-175, wherein theliquid composition comprising the bulking agent and crystals comprisesless than 0.5 percent of drug-degradent impurities relative to4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the liquidcomposition and less than 1 percent total impurities relative to the4-methyl-5-(pyrazin-2-yl)-3H-1, 2-dithiole-3-thione in the liquidcomposition.

180. A process according to any of embodiments 176 or 177, wherein thedry composition comprises less than 1 percent of drug-degradentimpurities relative to 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the liquid composition and less than 2 percenttotal impurities relative to the4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the liquidcomposition.

181. A process according to any of embodiments 176 or 177, wherein thedry composition comprising the bulking agent and crystals comprises lessthan 0.5 percent of drug-degradent impurities relative to4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the liquidcomposition and less than 1 percent total impurities relative to the4-methyl-5-(pyrazin-2-yl)-3H-1, 2-dithiole-3-thione in the liquidcomposition.

182. A process according to any of embodiments 128-181, wherein thepolydispersity index (PdI) of the crystals in the quantity is less than0.80, wherein PdI=(σ/d)², wherein σ is the standard deviation and d isthe mean hydrodynamic diameter (Z-average).

183. A process according to embodiment 182 wherein the polydispersityindex (PdI) of the crystals in the quantity is less than 0.60.

184. A process according to embodiment 182, wherein the polydispersityindex (PdI) of the crystals in the quantity is between 0.10 and 0.60.

185. A process according to embodiment 182, wherein the polydispersityindex (PdI) of the crystals in the quantity is between 0.10 and 0.45.

186. A process according to any of embodiments 128-185, wherein thequantity of crystals comprises substantially the entire quantity of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione present in the liquidcomposition.

187. A process comprising the steps of

-   -   providing a pharmaceutically acceptable container comprising a        cavity, and    -   adding to the container a dose of a dry pharmaceutical        composition, wherein the dry pharmaceutical composition        comprises a composition according to any of embodiments 1-39 and        64-99 that substantially excludes water,    -   wherein the cavity is of sufficient size to hold both the dry        pharmaceutical composition and an amount of a liquid sufficient        to permit mixing of the dry pharmaceutical composition with a        liquid to form a liquid pharmaceutical composition.

188. A process comprising the steps of

-   -   providing a pharmaceutically acceptable container comprising a        cavity, and    -   adding to the container a dose of a dry pharmaceutical        composition, wherein the dry pharmaceutical composition        comprises a dry composition prepared according to embodiment 176        or 177,    -   wherein the cavity is of sufficient size to hold both the dry        pharmaceutical composition and an amount of liquid sufficient to        permit mixing of the dry pharmaceutical composition with a        liquid to form a liquid pharmaceutical composition.

189. A process according to embodiment 187 or 188, wherein the containercomprises a compartment separate from the cavity, and the drypharmaceutical composition is added to the compartment.

190. A process according to any of embodiments 187-188, wherein thecontainer comprises a releasable coupling for uncoupling a portion ofthe container to provide an opening for dispensing a liquidpharmaceutical composition from the container.

191. A process according to embodiment 189, wherein the containerfurther comprises a releasable coupling for uncoupling a portion of thecontainer to provide an opening for dispensing a liquid composition fromthe container, and wherein the releasable coupling connects the portionof the container comprising the cavity to the portion of the containercomprising the compartment that contains the dose of a drypharmaceutical composition.

192. A process according to any of embodiments 189-191, wherein thecontainer further comprises a breakable seal between the compartment andthe cavity, and wherein the dry pharmaceutical composition remainsseparate from the cavity when said seal is unbroken, and wherein the drypharmaceutical composition can enter the cavity when the seal is broken.

193. A process according to any of embodiments 187-192, furthercomprises adding a liquid to the pharmaceutically acceptable containerand mixing the liquid and dry pharmaceutical composition.

194. A process comprising the steps of adding a liquid to the cavity ofa pharmaceutically acceptable container according to any of embodiments119-124, and mixing the dose of dry pharmaceutical composition with theliquid.

195. A process comprising the steps of adding a liquid to the cavity ofa pharmaceutically acceptable container according to embodiment 122-124,causing the dry pharmaceutical composition in the compartment to enterthe cavity, and mixing the dose of dry pharmaceutical composition withthe liquid.

196. A process comprising the steps of adding a liquid to the cavity ofa pharmaceutically acceptable container according to embodiment 124,breaking the seal between the compartment and the cavity and causing thedry pharmaceutical composition in the compartment to enter the cavity,and mixing the dose of dry pharmaceutical composition with the liquid.

197. A process according to any of embodiments 193-196, wherein theliquid further comprises at least one pharmaceutically acceptabletaste-modifying additive.

198. A process according to any of embodiments 193-197, wherein the stepof mixing is carried out by shaking the container for ten minutes orless.

199. A process according to any of embodiments 193-197, wherein the stepof mixing is carried out by shaking the container for five minutes orless.

200. A process according to any of embodiments 193-197, wherein the stepof mixing is carried out by shaking the container for three minutes orless.

201. A process according to any of embodiments 193-197, wherein the stepof mixing is carried out by shaking the container for two minutes orless.

202. A process according to any of embodiments 193-197, wherein the stepof mixing is carried out by shaking the container for one minute orless.

203. A process according to any of embodiments 193-202, wherein theliquid comprises water.

204. A process according to any of embodiments 193-203, wherein theliquid comprises a non-aqueous solvent.

205. A process for treating a human or non-human animal patient in needcomprising administering to the patient a composition prepared accordingto the process of any of embodiments 193-204.

206. A process for treating a human or non-human animal patient in needcomprising administering to the patient a pharmaceutical compositionaccording to any of embodiments 98-108.

207. A process according to embodiment 205 or 206, wherein theadministration comprises an oral administration.

208. A process according to embodiment 207, wherein the administrationcomprises a buccal administration

209. A process according to embodiment 208, wherein the buccaladministration comprises a swish and swallow administration.

210. A process according to embodiment 208, where the buccaladministration comprises a swish and spit administration.

211. A process for treating a human or non-human animal patient in needcomprising administering to the patient a pharmaceutical compositionaccording to any of embodiments 109-112.

212. A process for preventing, treating, ameliorating, lessening theseverity and/or shortening the duration of mucositis for a human ornon-human animal patient in need comprising orally administering apharmaceutical composition according to any of embodiments

115-118 to the patient.

213. A process for preventing, treating, ameliorating, lessening theseverity and/or shortening the duration of mucositis for a human ornon-human animal patient in need comprising orally administering anpharmaceutical composition prepared according to any of embodiments193-204.

214. A process for preventing, treating, ameliorating, lessening theseverity and/or shortening the duration of mucositis for a human ornon-human animal patient in need comprising orally administering to thepatient a pharmaceutical composition according to any of embodiments98-108.

215. A process according to any of embodiments 212-214, wherein themucositis in oral mucositis.

216. A process according to any of embodiments 212-214, wherein themucositis in mucositis of the alimentary canal.

217. A process for preventing, treating, ameliorating, lessening theseverity and/or shortening the duration of mucositis for a human ornon-human animal patient in need comprising topically administering acomposition according to embodiment 109.

218. A process for preventing, treating, ameliorating, lessening theseverity and/or shortening the duration of mucositis for a human ornon-human animal patient in need comprising rectally administering acomposition according to embodiment 110 or 111.

219. A process for preventing, treating, ameliorating, lessening theseverity and/or shortening the duration of mucositis for a human ornon-human animal patient in need comprising administering by inhalationa composition according to embodiment 112.

220. A process according to any of embodiments 205-219, wherein thepatient is undergoing radiation therapy.

221. A process according to embodiment 222, wherein the patient receivesadministration prior to the patient receiving his or her next radiationtreatment.

222. A process according to embodiment 221, wherein administration iscarried out one hour or less prior to the patient receiving a radiationtreatment.

223. A process according to embodiment 221, wherein administration iscarried out one day or less prior to the patient receiving a radiationtreatment.

224. A process according to any of embodiments 220-223, whereinadministration is carried out after the patient receives a radiationtreatment.

225. A process according to embodiment 224, wherein administration iscarried out within one hour after the patient receives a radiationtreatment.

226. A process according to embodiment 224, wherein administration iscarried out less within one day after the patient receives a radiationtreatment.

227. A process according to any of embodiments 205-226, wherein thecomposition comprising oltipraz is co-administered with at least onepharmaceutically acceptable agent selected from the group consisting ofantioxidants, agents that enhance glutathione synthesis, glutathione,Medihoney, NF-kappaB inhibitors, anti-inflammatory agents, and compoundsprevent damage from reactive O₂ ⁻ (superoxide).

228. A process according to any of embodiments 205-226, wherein thecomposition comprising oltipraz is co-administered with at least onepharmaceutically acceptable agent selected from the group consisting ofN acetylcysteine, pantothenic acid (vitamin B5), glutathione, Medihoney,curcumin, Mesalamine, and superoxide dismutase.

229. A process according to any of embodiments 205-226, wherein thecomposition comprising oltipraz is co-administered separately as part ofa dosing regimen with at least one pharmaceutically acceptable agentselected from the group consisting of antioxidants, agents that enhanceglutathione synthesis, glutathione, Medihoney, NF-kappaB inhibitors,anti-inflammatory agents, and compounds prevent damage from reactive O₂⁻ (superoxide).

230. A process according to any of embodiments 205-226, wherein thecomposition comprising oltipraz is co-administered separately as part ofa dosing regimen with at least one pharmaceutically acceptable agentselected from the group consisting of N acetylcysteine, pantothenic acid(vitamin B5), glutathione, Medihoney, curcumin, Mesalamine, andsuperoxide dismutase.

231. A composition according to any of embodiments 40-112, wherein thesolubility of the crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the composition isat least 5.0 μg/ml of water at 20° C.

232. A composition according to any of embodiments 40-108, wherein thesolubility of the crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the composition isat least 5.5 μg/ml of water at 20° C.

233. A composition according to any of embodiments 40-108, wherein thesolubility of the crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the composition isbetween 5.5 μg/ml of water and 6.0 μg/ml of water at 20° C.

234. A composition according to any of embodiments 40-108, wherein thesolubility of the crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the composition isbetween 6.0 μg/ml of water and 8.0 μg/ml of water at 20° C.

235. A pharmaceutically acceptable container according to any ofembodiments 119-127, wherein the solubility of the crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the composition isat least 5.0 μg/ml of water at 20° C.

236. A pharmaceutically acceptable container according to any ofembodiments 119-127, wherein the solubility of the crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the composition isat least 5.5 μg/ml of water at 20° C.

237. A pharmaceutically acceptable container according to any ofembodiments 119-127, wherein the solubility of the crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the composition isbetween 5.5 μg/ml of water and 6.0 μg/ml of water at 20° C.

238. A pharmaceutically acceptable container according to any ofembodiments 119-127, wherein the solubility of the crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione in the composition isbetween 6.0 μg/ml of water and 8.0 μg/ml of water at 20° C.

239. A process according to any of embodiments 128-230, wherein thesolubility of the crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione is at least 5.0 μg/mlof water at 20° C.

240. A process according to any of embodiments 128-230, wherein thesolubility of the crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione is at least 5.5 μg/mlof water at 20° C.

241. A process according to any of embodiments 128-230, wherein thesolubility of the crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione is between 5.5 μg/mlof water and 6.0 μg/ml of water at 20° C.

242. A process according to any of embodiments 128-230, wherein thesolubility of the crystals of4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione is between 6.0 and8.0 μg/ml of water at 20° C.

243. A process for increasing the gene expression of glutathioneperoxidase 4 (GPX4) and/or myeloperoxidase (MPO) in a human or non-humananimal patient comprising administering a pharmaceutical compositionaccording to any of the embodiments 89-112 to the patient.

244. A process for decreasing the gene expression of Peroxiredoxin 2(PRDX2) in a human or non-human animal patient comprising administeringa pharmaceutical composition according to any of the embodiments 89-112to the patient.

245. A process for increasing the gene expression of glutathioneperoxidase 4 (GPX4) and/or myeloperoxidase (MPO) and decreasing the geneexpression of Peroxiredoxin 2 (PRDX2) in a human or non-human animalpatient comprising administering a pharmaceutical composition accordingto any of the embodiments 89-112 to the patient.

246. A process for increasing the gene expression of glutathioneperoxidase 4 (GPX4) and/or myeloperoxidase (MPO) in a human or non-humananimal patient comprising administering a pharmaceutical compositionaccording to any of the embodiments 187-204 to the patient.

247. A process for decreasing the gene expression of Peroxiredoxin 2(PRDX2) in a human or non-human animal patient comprising administeringa pharmaceutical composition according to any of the embodiments 187-204to the patient.

248. A process for increasing the gene expression of glutathioneperoxidase 4 (GPX4) and/or myeloperoxidase (MPO) and decreasing the geneexpression of Peroxiredoxin 2 (PRDX2) in a human or non-human animalpatient comprising administering a pharmaceutical composition accordingto any of the embodiments 187-204 to the patient.

249. A process according to any of embodiments 243 to 248, wherein thepatient is undergoing chemotherapy and/or radiation therapy.

250. A process according to embodiment 249, wherein the patient hasmucositis.

251. A process according to embodiment 250, wherein the mucositis isoral mucositis.

252. A process for decreasing intracellular reactive oxygen species(ROS) and/or decreasing oxidative stress in a human or non-human animalpatient comprising administering a pharmaceutical composition accordingto any of the embodiments 89-112 to the patient.

253. A process for decreasing intracellular reactive oxygen species(ROS) and/or decreasing oxidative stress in a human or non-human animalpatient comprising administering a pharmaceutical composition accordingto any of the embodiments 187-204 to the patient.

254. A process according to embodiment 252 or 253, wherein the patientis undergoing treatments that provide oxidative stress such aschemotherapy or radiation therapy.

255. A process according to any of embodiments 252-254, wherein theoxidative stress results in or contributes to mucositis in the patient.

256. A process according to embodiment 255, wherein the mucositis isoral mucositis.

257. A process for providing an antioxidant effect in a human ornon-human animal patient comprising administering a pharmaceuticalcomposition according to any of the embodiments 89-112 to the patient.

258. A process for providing an antioxidant effect in a human ornon-human animal patient comprising administering a pharmaceuticalcomposition according to any of the embodiments 187-204 to the patient.

259. A process according to embodiment 257 or 258, wherein the patientis undergoing chemotherapy or radiation therapy.

260. A process according to any of embodiments 257-259, wherein thepatient has mucositis.

261. A process according to embodiment 260, wherein the mucositis isoral mucositis.

262. A process for providing one or more effects selected from the groupconsisting of slowing the onset of oxidative damage, reducing theseverity of oxidative damage, and/or reducing the duration of oxidativedamage in a human or non-human animal patient comprising administering apharmaceutical composition according to any of the embodiments 89-112 tothe patient.

263. A process for providing one or more effects selected from the groupconsisting of slowing the onset of oxidative damage, reducing theseverity of oxidative damage, and/or reducing the duration of oxidativedamage in a human or non-human animal patient comprising administering apharmaceutical composition according to any of the embodiments 187-204to the patient.

264. A process according to embodiment 262 or 263, wherein the patientis undergoing chemotherapy and/or radiation therapy.

265. A process according to any of embodiments 262-264, wherein thepatient has mucositis.

266. A process according to embodiment 265, wherein the mucositis isoral mucositis.

Definitions

For convenience, certain terms employed in the specification andappended claims are collected here. These definitions should be read inlight of the entire disclosure and understood as by a person of skill inthe art.

The articles “a” and “an,” as used herein in the specification and inthe claims, unless clearly indicated to the contrary, should beunderstood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

The phrase “or,” as used herein in the specification and in the claims,should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“or” should be construed in the same fashion, i.e., “one or more” of theelements so conjoined. Other elements may optionally be present otherthan the elements specifically identified by the “or” clause, whetherrelated or unrelated to those elements specifically identified. Thus, asa non-limiting example, a reference to “A or B”, when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A only (optionally including elements other than B);in another embodiment, to B only (optionally including elements otherthan A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to thecontrary, processes described herein and claimed below can include stepsin addition to the steps recited, and the order of the steps or acts ofthe process is not necessarily limited to the order in which the stepsor acts of the process are recited. In the context of this disclosure,the words “process” and “method” are synonymous.

In the claims, as well as in the specification, all transitional phrasessuch as “comprising,” “comprised of,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments described herein. Such equivalents are intended to beencompassed by the following claims.

1. A composition comprising a quantity of crystals of4-methyl-5-(pyrazin-2-yl)-3H-1, 2-dithiole-3-thione having an intensityaveraged, mean hydrodynamic diameter (Z-average) (“MHD”) of from 30 to2000 nm, as measured by dynamic light scattering at 25° C. on asuspension of the crystals in water at a concentration of 0.01 to 0.1 mgof crystals per mL of water.
 2. A composition comprising a quantity ofcrystals according to claim 1 wherein the MHD is from about 30 to about1200 nm, preferably from about 100 to about 600 nm, more preferably fromabout 150 to about 450 nm.
 3. A composition comprising a quantity ofcrystals according to claim 2 wherein the polydispersity index (PdI) ofthe crystals, defined as PdI=(σ/d)², wherein σ is the standard deviationand d is the mean hydrodynamic diameter (Z-average) of the crystals, isfrom about 0.10 to about 0.60, preferably from about 0.1 to about 0.45,more preferably from about 0.1 to about 0.35.
 4. A compositioncomprising a quantity of crystals according to claim 3, wherein thesolubility of the crystals in water at 20° C. is from about 3.5 to about8 μg/ml, preferably from about 4.5 to about 7 μg/ml, more preferablyfrom about 5 to about 6.5 μg/ml.
 5. A composition comprising crystalsaccording to claim 1 and a stabilizing agent, wherein the stabilizingagent comprises: i) a polymeric stabilizing agent selected from anacrylate- and alkenyl ether-based co-polymer (e.g., Carbopol® typepolymers such as Carbopol 974P NF), polyvinylpyrrolidine (e.g., PVP K15or K30), a cellulosic polymer such as a cationic hydroxyethyl cellulose(e.g., in the Polymer JR family), hydroxypropylcellulose (HPC e.g. HPCEF typically having a molecular weight of about 80 kDa), hydroxypropylmethylcellulose (HPMC e.g. HMPC E3 typically having viscosity of about 3cP at 2% in water), hydroxypropyl methylcellulose acetate succinate,HPMCAS, a copovidone (e.g., PVP-VA64), poly(ethylene oxide), a poloxamer(e.g., a poly(propylene oxide) and poly(ethylene oxide) copolymer), anacrylamide polymer, or poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2(“EUDRAGIT® RL”); and/or ii) a surfactant selected from sodiumisostearate, cetyl alcohol, polysorbates (Polysorbate 20, Polysorbate40, Polysorbate 60, Polysorbate 80), steareth-10 (Brij 76), sodiumdodecyl sulfate (sodium lauryl sulfate), lauryl dimethyl amine oxide,cetyltrimethylammonium bromide (CTAB), polyethoxylated alcohols,polyoxyethylene sorbitan, octoxynol, N,N-dimethyldodecylamine-N-oxide,hexadecyltrimethylammonium bromide (HTAB), polyoxyl 10 lauryl ether,bile salts (such as sodium deoxycholate or sodium cholate), polyoxylcastor oil, nonylphenol ethoxylate, cyclodextrins, lecithin, dimethiconecopolyol, lauramide DEA, cocamide DEA, cocamide MEA, oleyl betaine,cocamidopropyl betaine, cocamidopropyl phosphatidyl PG-dimoniumchloride, dicetyl phosphate (dihexadecyl phosphate), ceteareth-10phosphate, methylbenzethonium chloride, dicetyl phosphate, ceteth-10phosphate, ceteth-20, Brij S10 (polyethylene glycol octadecyl ether,average M_(n)˜711), PEG-20 phytosterol, Poloxamers such as Poloxamer 188and Poloxamer 407 (e.g., “Pluronic F-68”), polyoxyethylene glycol alkylethers (e.g., octaethylene glycol monododecyl ether, pentaethyleneglycol monododecyl ether, and polyethylene glycol alkyl ethers such asBrij® Detergents), polyoxypropylene glycol alkyl ethers, glucoside alkylethers (e.g., decyl glucoside, lauryl glucoside, or octyl glucoside),polyoxyethylene glycol alkylphenol ethers (e.g. Triton X-100,Nonoxyol-9), glycerol alkyl esters, polyoxyethylene glycol sorbitanalkyl esters (e.g., polysorbates), sorbitan alkyl esters, cocamides, andpolyoxyethylene (20) sorbitan monooleate (polysorbate 80, also known as“Tween 80”).
 6. A composition according to claim 5 further comprising abulking agent, wherein bulking agent is selected frompolyvinylpyrrolidones (e.g., PVP K30 and PVP-VA64), cellulosic polymerssuch as HPC, HPMC, HPMC E3, Trehalose, and Dextrans such as Dextran 10or Dextran
 40. 7. A composition according to claim 5 which is in liquidform, wherein the composition preferably comprises water and/or anon-aqueous solvent.
 8. A composition according to claim 5 which is indry form, wherein the composition substantially excludes water and anynon-aqueous solvent.
 9. A liquid composition according to claim 7wherein the composition does not comprise a bulking agent, and wherein:i) the composition comprises between about 1 to about 40 wt % ofoltipraz crystals, based on the weight of the liquid composition; ii)the non-solvent components in the composition typically comprise fromabout 1 to about 70 wt % oltipraz crystals; and iii) the compositioncomprises (i) from about 5 to about 40 wt % (based on the weight ofsolid components in the composition) of one or more of acrylate- andalkenyl ether-based co-polymers, polyvinylpyrrolidone,hydroxypropylcellulose, hydroxypropyl methylcellulose, a copovidone suchas PVP-VA64, and a polymethacrylate-based copolymer such as EUDRAGIT®RL; and/or (ii) from about 10 to about 20 wt % % (based on the weight ofsolid components in the composition) of one or more of sodium laurylsulfate, a poloxamer such as Pluronic F-68 and polysorbate
 80. 10. Aliquid composition according to claim 9 wherein: i) the compositioncomprises between about 7 to about 10 wt % of oltipraz crystals, basedon the weight of the liquid composition; ii) the non-solvent componentsin the composition typically comprise from about 55 to about 58 wt %oltipraz crystals; iii) the composition comprises (i) from about 25 toabout 30 wt % (based on the weight of solid components in thecomposition) of one or more of a copovidone such as PVP-VA64 and apolymethacrylate-based copolymer such as EUDRAGIT® RL; and/or (ii) fromabout 14 to about 15 wt % % (based on the weight of solid components inthe composition) of polysorbate 80 (Tween 80); iv) the liquid solvent iswater; and v) the composition optionally comprises 0.1 to 1 wt %simethicone based on the non-solvent components in the composition. 11.A liquid composition according to claim 7 comprising a bulking agentwherein: i) the concentration of oltipraz crystals in the liquid is fromabout 0.1 to about 10 wt % based on the weight of the liquidcomposition; ii) the non-solvent components in the composition typicallycomprise from about 0.5 to about 25 wt % oltipraz crystals; iii) thecomposition comprises (i) from about 5 to about 40 wt % (based on theweight of solid components excluding bulking agents in the composition)of one or more of acrylate- and alkenyl ether-based co-polymers,polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, a copovidone such as PVP-VA64, and apolymethacrylate-based copolymer such as EUDRAGIT® RL; and/or (ii) fromabout 10 to about 20 wt % % (based on the weight of solid componentsexcluding bulking agents in the composition) of one or more of sodiumlauryl sulfate, a poloxamer such as Pluronic F-68 and polysorbate 80;and iv) the composition comprises from about 1 to about 40 wt % (basedon the overall weight of the composition) of a bulking agent selectedfrom polyvinylpyrrolidones (e.g., PVP K30 and PVP-VA64), cellulosicpolymers such as HPC, HPMC, HPMC E3, Trehalose, Dextrans (such asDextran 10 or Dextran 40), PVP-VA64 and HPC EF.
 12. A liquid compositionaccording to claim 11 wherein: i) the concentration of oltipraz crystalsin the liquid is from about 2 to about 5 wt % based on the weight of theliquid composition; ii) the non-solvent components in the compositiontypically comprise from about 10 to about 18 wt % oltipraz crystals;iii) the composition comprises (i) from about 25 to about 30 wt % (basedon the weight of solid components excluding bulking agents in thecomposition) of one or more of a copovidone such as PVP-VA64 and apolymethacrylate-based copolymer such as EUDRAGIT® RL; and/or (ii) fromabout 14 to about 15 wt % % (based on the weight of solid componentsexcluding bulking agents in the composition) of polysorbate 80 (Tween80); iv) the composition comprises from about 15 to about 25 wt % (basedon the overall weight of the composition) of a bulking agent which isPVP-VA64; v) the liquid solvent is water; and vi) the compositionoptionally comprises 0.1 to 1 wt % simethicone based on the non-solventcomponents (excluding the bulking agent) in the composition.
 13. A drycomposition according to claim 8 comprising a bulking agent, wherein: i)the percentage of oltipraz in the composition (i.e. the drug loading) isfrom about 12 to about 20 wt %; ii) the composition comprises (i) fromabout 5 to about 40 wt % (based on the weight of solid componentsexcluding bulking agents in the composition) of one or more of acrylate-and alkenyl ether-based co-polymers, polyvinylpyrrolidone,hydroxypropylcellulose, hydroxypropyl methylcellulose, a copovidone suchas PVP-VA64, and a polymethacrylate-based copolymer such as EUDRAGIT®RL; and/or (ii) from about 10 to about 20 wt % % (based on the weight ofsolid components excluding bulking agents in the composition) of one ormore of sodium lauryl sulfate, a poloxamer such as Pluronic F-68 andpolysorbate 80; and iii) the composition comprises from about 40 toabout 90 wt % (based on the overall weight of the composition) of abulking agent selected from polyvinylpyrrolidones (e.g., PVP K30 andPVP-VA64), cellulosic polymers such as HPC, HPMC, HPMC E3, Trehalose,Dextrans (such as Dextran 10 or Dextran 40), PVP-VA64 and HPC EF.
 14. Adry composition according to claim 13, wherein: i) the percentage ofoltipraz in the composition (i.e. the drug loading) is from about 15 toabout 17 wt %; ii) the composition comprises (i) from about 25 to about30 wt % (based on the weight of solid components excluding bulkingagents in the composition) of one or more of a copovidone such asPVP-VA64 and a polymethacrylate-based copolymer such as EUDRAGIT® RL;and/or (ii) from about 14 to about 15 wt % % (based on the weight ofsolid components excluding bulking agents in the composition) ofpolysorbate 80 (Tween 80); and iii) the composition comprises from about70 to about 78 wt % (based on the overall weight of the composition) ofa bulking agent which is PVP-VA64; and iv) the composition optionallycomprises 0.1 to 1 wt % simethicone based on the weight of solidcomponents excluding bulking agents in the composition.
 15. A suspensionof crystals according to claim 1 in aqueous solution wherein the ratioof the crystals or the composition to the solution is from 1:10 to1:200.
 16. A pharmaceutical composition comprising a composition ofcrystals according to claim 1 wherein: i) the composition is in liquiddosage form and comprises at least one pharmaceutically acceptablediluent, adjuvant; suspending agent and/or carrier; or ii) thecomposition is in dry dosage form and comprises at least onepharmaceutically acceptable additive, lubricant, excipient or diluent.17-19. (canceled)
 20. A kit comprising: i) a composition comprising aquantity of crystals according to claim 1; and ii) either (A) a devicefor oral administration of the crystals, composition, suspension,pharmaceutical composition or crystals, composition, suspension orpharmaceutical composition for use; or (B) an inhaler device foradministration of the crystals, composition, suspension, pharmaceuticalcomposition or crystals, composition, suspension or pharmaceuticalcomposition for use by inhalation.
 21. A process for producing acomposition comprising a quantity of crystals according to claim 1 theprocess comprising: i) wet milling a composition comprising a liquid and4-methyl-5-(pyrazin-2-yl)-3H-1, 2-dithiole-3-thione to produce a liquidcomposition comprising crystals having an intensity averaged, meanhydrodynamic diameter (Z-average) (“MHD”) of from 30 to 2000 nm, asmeasured by dynamic light scattering at 25° C. on a suspension of thecrystals in water at a concentration of 0.01 to 0.1 mg of crystals permL of water.
 22. A process according to claim 21 wherein the compositioncomprises a stabilizing agent, the stabilizing agent comprising a) apolymeric stabilizing agent selected from an acrylate- and alkenylether-based co-polymer (e.g., Carbopol® type polymers such as Carbopol974P NF), polyvinylpyrrolidine (e.g., PVP K15 or K30), a cellulosicpolymer such as a cationic hydroxyethyl cellulose (e.g., in the PolymerJR family), hydroxypropylcellulose (HPC e.g. HPC EF typically having amolecular weight of about 80 kDa), hydroxypropyl methylcellulose (HPMCe.g. HMPC E3 typically having viscosity of about 3 cP at 2% in water),hydroxypropyl methylcellulose acetate succinate, HPMCAS, a copovidone(e.g., PVP-VA64), poly(ethylene oxide), a poloxamer (e.g., apoly(propylene oxide) and poly(ethylene oxide) copolymer), an acrylamidepolymer, or poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2(“EUDRAGIT® RL”); and/or b) a surfactant selected from sodiumisostearate, cetyl alcohol, polysorbates (Polysorbate 20, Polysorbate40, Polysorbate 60, Polysorbate 80), steareth-10 (Brij 76), sodiumdodecyl sulfate (sodium lauryl sulfate), lauryl dimethyl amine oxide,cetyltrimethylammonium bromide (CTAB), polyethoxylated alcohols,polyoxyethylene sorbitan, octoxynol, N,N-dimethyldodecylamine-N-oxide,hexadecyltrimethylammonium bromide (HTAB), polyoxyl 10 lauryl ether,bile salts (such as sodium deoxycholate or sodium cholate), polyoxylcastor oil, nonylphenol ethoxylate, cyclodextrins, lecithin, dimethiconecopolyol, lauramide DEA, cocamide DEA, cocamide MEA, oleyl betaine,cocamidopropyl betaine, cocamidopropyl phosphatidyl PG-dimoniumchloride, dicetyl phosphate (dihexadecyl phosphate), ceteareth-10phosphate, methylbenzethonium chloride, dicetyl phosphate, ceteth-10phosphate, ceteth-20, Brij S10 (polyethylene glycol octadecyl ether,average M_(n)˜711), PEG-20 phytosterol, Poloxamers such as Poloxamer 188and Poloxamer 407 (e.g., “Pluronic F-68”), polyoxyethylene glycol alkylethers (e.g., octaethylene glycol monododecyl ether, pentaethyleneglycol monododecyl ether, and polyethylene glycol alkyl ethers such asBrij® Detergents), polyoxypropylene glycol alkyl ethers, glucoside alkylethers (e.g., decyl glucoside, lauryl glucoside, or octyl glucoside),polyoxyethylene glycol alkylphenol ethers (e.g. Triton X-100,Nonoxyol-9), glycerol alkyl esters, polyoxyethylene glycol sorbitanalkyl esters (e.g., polysorbates), sorbitan alkyl esters, cocamides, andpolyoxyethylene (20) sorbitan monooleate (polysorbate 80, also known as“Tween 80”), and wherein optionally the process further comprises ii)adding a bulking agent, wherein the bulking agent is selected frompolyvinylpyrrolidones (e.g., PVP K30 and PVP-VA64), cellulosic polymerssuch as HPC, HPMC, HPMC E3, Trehalose, and Dextrans such as Dextran 10or Dextran 40 to the liquid composition comprising crystals produced instep (i).
 23. A process according to claim 22 further comprising: iii)removing the liquid from the liquid composition comprising crystals toform a dry composition, wherein preferably removing the liquid from theliquid composition comprises the step of spray-drying or lyophilizingthe liquid composition.